Fe(III) complex compounds for the treatment and prophylaxis of iron deficiency symptoms and iron deficiency anemias

ABSTRACT

The invention relates to iron(III) complex compounds and pharmaceutical compositions comprising them for the use as medicaments, in particular for the treatment and/or prophylaxis of iron deficiency symptoms and iron deficiency anemias.

INTRODUCTION

The invention relates to iron(III)-β-ketoamide complex compounds andpharmaceutical compositions comprising them for the use as medicaments,in particular for the treatment and/or prophylaxis of iron deficiencysymptoms and iron deficiency anemias.

BACKGROUND

Iron is an essential trace element for almost all organisms and isrelevant in particular with respect to growth and the formation ofblood. The balance of the iron metabolism is in this case primarilyregulated on the level of iron recovery from hemoglobin of ageingerythrocytes and the duodenal absorption of dietary iron. The releasediron is taken up via the intestine, in particular via specific transportsystems (DMT-1, ferroportin, transferrin, transferrin receptors),transferred into the circulation and thereby conveyed to the appropriatetissues and organs.

In the human body, the element iron is of great importance for oxygentransport, oxygen uptake, cell functions such as mitochondrial electrontransport, and ultimately for the entire energy metabolism.

On average, the human body contains 4 to 5 g iron, with it being presentin enzymes, in hemoglobin and myoglobin, as well as depot or reserveiron in the form of ferritin and hemosiderin.

Approximately half of this iron, about 2 g, is present as heme iron,bound in the hemoglobin of the erythrocytes. Since these erythrocyteshave only a limited lifespan (75-150 days), new ones have to be formedconstantly and old ones eliminated (over 2 million erythrocytes arebeing formed per second). This high regenerative capacity is achieved bymacrophages phagocytizing the ageing erythrocytes, lysing them and thusrecycling the iron thus obtained for the iron metabolism. The amount ofiron of about 25 mg required daily for erythropoiesis is thus providedfor the main part.

The daily iron requirement of an adult human is between 0.5 to 1.5 mgper day, infants and women during pregnancy require 2 to 5 mg of ironper day. The daily iron loss, e.g. by desquamation of skin andepithelial cells, is low; increased iron loss occurs, for example,during menstrual hemorrhage in women. Generally, blood loss cansignificantly reduce the iron level since about 1 mg iron is lost per 2ml blood. In a healthy human adult, the normal daily loss of iron ofabout 1 mg is usually replaced via the daily food intake. The iron levelis regulated by absorption, with the absorption rate of the iron presentin food being between 6 and 12%; in the case of iron deficiency, theabsorption rate is up to 25%. The absorption rate is regulated by theorganism depending on the iron requirement and the size of the ironstore. In the process, the human organism utilizes both divalent as wellas trivalent iron ions. Usually, iron(III) compounds are dissolved inthe stomach at a sufficiently acid pH value and thus made available forabsorption. The absorption of the iron is carried out in the upper smallintestine by mucosal cells. In the process, trivalent non-heme iron isfirst reduced in the intestinal cell membrane to Fe(II) for absorption,for example by ferric reductase (membrane-bound duodenal cytochrome b),so that it can then be transported into the intestinal cells by means ofthe transport protein DMT1 (divalent metal transporter 1). In contrast,heme iron enters the enterocytes through the cell membrane without anychange. In the enterocytes, iron is either stored in ferritin as depotiron, or discharged into the blood by the transport protein ferroportin.Hepcidin plays a central role in this process because it is the mostimportant regulating factor of iron uptake. The divalent irontransported into the blood by ferroportin is converted into trivalentiron by oxidases (ceruloplasmin, hephaestin), the trivalent iron thenbeing transported to the relevant places in the organism by transferrin(see for example “Balancing acts: molecular control of mammalian ironmetabolism”. M. W. Hentze, Cell 117, 2004, 285-297.)

Mammalian organisms are unable to actively discharge iron. The ironmetabolism is substantially controlled by hepcidin via the cellularrelease of iron from macrophages, hepatocytes and enterocytes.

In pathological cases, a reduced serum iron level leads to a reducedhemoglobin level, reduced erythrocyte production and thus to anemia.

External symptoms of anemias include fatigue, pallor as well as reducedcapacity for concentration. The clinical symptoms of an anemia includelow serum iron levels (hypoferremia), low hemoglobin levels, lowhematocrit levels as well as a reduced number of erythrocytes, reducedreticulocytes and elevated levels of soluble transferrin receptors.

Iron deficiency symptoms or iron anemias are treated by supplying iron.In this case, iron substitution takes place either orally or byintravenous iron administration. Furthermore, in order to boosterythrocyte formation, erythropoietin and othererythropoiesis-stimulating substances can also be used in the treatmentof anemias.

Anemia can often be traced back to malnutrition or low-iron diets orimbalanced nutritional habits low in iron. Moreover, anemias occur dueto reduced or poor iron absorption, for example because ofgastroectomies or diseases such as Crohn's disease. Moreover, irondeficiency can occur as a consequence of increased blood loss, such asbecause of an injury, strong menstrual bleeding or blood donation.Furthermore, an increased iron requirement in the growth phase ofadolescents and children as well as in pregnant women is known. Sinceiron deficiency not only leads to a reduced erythrocyte formation, butthereby also to a poor oxygen supply of the organism, which can lead tothe above-mentioned symptoms such as fatigue, pallor, reduced powers ofconcentration, and especially in adolescents, to long-term negativeeffects on cognitive development, a highly effective and well toleratedtherapy is of particular interest.

Through using the Fe(III) complex compounds according to the invention,there is the possiblity of treating iron deficiency symptoms and irondeficiency anemias effectively by oral application without having toaccept the large potential for side effects of the classicalpreparations, the Fe(II) iron salts, such as FeSO₄, which is caused byoxidative stress. Poor compliance, which often is the reason for thedeficient elimination of the iron deficiency condition, is thus avoided.

PRIOR ART

A multitude of iron complexes for the treatment of iron deficiencyconditions is known from the prior art.

A very large proportion of these complex compounds consists of polymerstructures. Most of these complex compounds are iron-polysaccharidecomplex compounds (WO20081455586, WO2007062546, WO20040437865,US2003236224, EP150085). It is precisely from this area that there aremedicaments available on the market (such as Maltofer, Venofer,Ferinject, Dexferrum, Ferumoxytol).

Another large portion of the group of the polymer complex compounds iscomprised of the iron-peptide complex compounds (CN101481404, EP939083,JP02083400).

There are also Fe complex compounds described in the literature that arestructurally derived from macromolecules such as hemoglobin,chlorophyll, curcumin and heparin (US474670, CN1687089, Biometals, 2009,22, 701-710).

Moreover, low-molecular Fe complex compounds are also described in theliterature. A large number of these Fe complex compounds comprisescarboxylic acid and amino acids as ligands. In this case, the focus ison aspartate (US2009035385) and citrate (EP308362) as ligands. Fecomplex compounds containing derivatized phenylalanine groups as ligandsare also described in this context (ES2044777).

Furthermore, Fe complex compounds that are composed of monomeric sugarunits or of a combination or monomeric and polymeric units are describedin the literature (FR19671016).

Hydroxypyrone and hydroxypyridone Fe complex compounds are alsodescribed in the literature (EP159194, EP138420, EP107458). Thecorresponding 5-ring systems, the hydroxyfuranone Fe complex compounds,are also described in analogy thereto (WO2006037449).

Moreover, iron-cyclopentadienyl complex compounds are also described inthe literature (GB842637).

Furthermore, β-ketoamides as Fe ligands are also described in theliterature. However, the compounds were not proposed or used asmedicaments, in particular for a treatment of iron deficiencyconditions. These are ketoamide structural units that are a constituentof siderophores (JACS, 2008, 130, 2124-2125). Furthermore, hexadentateferric aerobactin complex compounds (Inorg. chem. 2006, 45, 6028-6033)were described. Moreover, tripodal Fe ligands with β-ketoamidestructural units are disclosed in the literature (Inorg. chem. 1990, 29,4096-9).

Furthermore, β-ketoamides as Fe ligands which carry aromatic groups onthe amide or the ketone and are present as Fe(III) complexes aredescribed in the literature (Journal of the Chemical Society ofPakistan, 1991, 13, 79-83; Indian Journal of Chemistry, 1981, 20A,372-4; Journal of Inorganic and Nuclear Chemistry, 1973, 35, 1397-400;Can J Chem, 1969, 47, 1693-6; Indian Journal of Chemistry, 1968, 6,516-20).

Moreover, β-ketoamides as Fe(II) ligands containing pyridin groups(Journal of Inorganic and Nuclear Chemistry, 1967, 29, 2484-6),benzyloxazolidinones or substituted sultam groups (Polyhedron, 1995, 14,1397-9) are described in the literature.

US2005/0192315 describes salts of quinoline compounds which arestabilized against the neutral forms of the quinoline compounds (seeSections 2 and 3). Among the salts there is also theN-ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamideiron (III) salt. The document mentions also pharmaceutical compositions.However, throughout the document no specific medical indication ismentioned, let alone supported by any data. A medical use of iron(III)-β-ketoamide complex compounds is therefore not taught in thisdocument. As far as a medical use ofN-ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamideiron (III) salt should be taught by this document, it is excluded fromthe present invention. In Syamal, A.: “Ferric benzoylacetanilides”Canadian Journal of Chemistry, 47 (10), 1969, 1693-6, only the synthesisand spectroscopic properties of individual benzoylacetanilide-ironcomplex compounds is described.

The use of these complexes for the treatment and prophylaxis of irondeficiency symptoms and iron deficiency anemias is described in none ofthe passages cited in the text above.

Iron salts (e.g. iron(II) sulfate, iron(II) fumarate, iron(III)chloride, iron(II) aspartate, iron(II) succinate) are another importantconstituent for the treatment of iron deficiency symptoms and irondeficiency anemias.

These iron salts are very problematic in that, in part, they are highlyincompatible (up to 50%) in the form of nausea, vomiting, diarrhea andalso obstipation and cramps. Moreover, free iron(II) ions which catalyzethe formation (inter alia Fenton reaction) of reactive oxygen species(ROS) occur during the use of these iron(II) salts. These ROS causedamage to DNA, lipids, proteins and carbohydrates which has far-reachingeffects in cells, tissue and organs. This complex of problems is knownand, in the literature, is largely considered the cause for the highincompatibility and referred to as oxidative stress.

OBJECT

The object of the present invention lay in developing newtherapeutically effective compounds that can be used for an effectivetherapy for the preferably oral treatment of iron deficiency symptomsand iron deficiency anemias. In this case, these iron complexes weresupposed to exhibit significantly fewer side effects than theclassically used Fe(II) salts. Furthermore, these iron complexes, incontrast to the known polymeric iron complex compounds, were, ifpossible, supposed to have a defined structure (stoichiometry) and bepreparable by simple synthesis processes. This goal was achieved by thedevelopment of novel Fe(III) complex compounds.

Furthermore, the novel iron complexes were supposed to be designed suchthat they are taken up into the intestinal cells directly via themembrane in order thus to release their complex-bound iron directly tothe ferritin or the transferrin or to reach the bloodstream directly asan intact complex. Because of their properties, these new complexes aresupposed to virtually not lead to the occurrence of high concentrationsof free iron ions. For it is precisely the free iron ions that lead tothe occurrence of ROS which are ultimately responsible for the sideeffects that occur.

In order to be able to meet these requirements, the inventors developednew Fe(III) complex compounds with a molecular weight that is not toolarge, medium lipophila and an optimal complex stability.

DESCRIPTION OF THE INVENTION

The inventors found that Fe(III) complex compounds with β-ketoamideligands were particularly suitable for the above-described requirements.It was possible to demonstrate that these Fe complex compounds exhibiteda high iron uptake, whereby a quick therapeutic success in the treatmentof iron deficiency anemia could be achieved. Especially in comparison toiron salts, the complex compounds according to the invention exhibited afaster and higher utilization. Furthermore, these new systems havesignificantly reduced side effects than the classically used iron saltssince there is no noteworthy occurrence of free iron ions in this case.The complex compounds according to the invention exhibit almost nooxidative stress since there is no formation of free radicals. Thus,significantly fewer side effects occur in the case of these complexcompounds than in the case of the Fe salts known from the prior art. Thecomplex compounds exhibit good stability at various pH value ranges. Thecomplex compounds can be prepared well and are optimally suitable forthe formulation of medicaments, in particular for oral administration.

Thus, the subject matter of the invention are iron(III)-β-ketoamidecomplex compounds or their pharmaceutically acceptable salts for use asmedicaments. Subject matter of the invention are therefore also iron(III)-β-ketoamide complex compounds or their pharmaceutically acceptablesalts for use in a method for therapeutic treatment of the human oranimal body.

The iron(III)-β-ketoamide complex compounds in particular include suchcompounds which comprise the following structural element:

or its mesomeric resonance formula:

wherein

respectively is a substituent saturating the free valence and the arrowsrespectively represent coordinate bonds. Formally, a β-ketoamide ligandcarries a negative charge and iron a positive charge (i.e., in the caseof three β-ketoamide ligands, the iron formally has the oxidation number+3). Furthermore, it is clear to the person skilled in the art that adelocalization of the electrons occurs in the β-ketoamide ligand.

According to the invention, iron(III)-β-ketoamide complex compounds arealso comprised in which the β-ketoamide ligand forms a bridge betweendifferent iron atoms:

According to the invention, in particular bidentate β-ketomide ligandsare preferred in which the bonding to the iron atom occurs via the twooxygen atoms of the β-keto structural unit. Though higher-dentateβ-ketoamide ligands such as tridentate, tetradentate, pentadentate oreven hexadentate β-ketoamide ligands are comprised in the presentinvention, they are less preferred due to their high complex stability(chelate effect) because possibly, iron is not released in a sufficientextent in the body due to the complex stabilities being too high.Higher-dentate β-ketoamide ligands are in particular those which,besides the two oxygen atoms of the β-ketoamide structure, comprisefurther functional coordinating groups, which are present, for example,in the substituent groups R¹ to R⁴ explained below. These can be, forexample, oxygen or nitrogen-containing functional groups, such ashydroxy, amino or the like.

The iron(III)-β-ketoamide complex compounds according to the inventioninclude, in particular, such complex compounds that have at least one,preferably bidentate, β-ketoamide ligand bonded to one or two differentiron atoms, as shown above.

Iron(III)-β-ketoamide complex compounds are preferred which exclusivelycomprise preferably bidentate β-ketoamide ligands that can be the sameor different.

Furthermore, iron(III)-β-ketoamide complex compounds are particularlypreferred which exclusively comprise the same, preferably bidentateβ-ketoamide ligands.

According to the invention, however, also such complex compounds arecomprised, which, besides the β-ketoamide ligand, preferably have one ormore (such as two or three) mono- or polydentate ligands that are thesame or different, such as, for example, carboxylic acid or carboxylateligands (R—COOH bzw. RCOO⁻), alcohol ligands (R—OH), such ascarbohydrate ligands, primary or secondary amino ligands (R—NH₂, R—NHR),imino ligands (R═NH), oximo ligands (R═N—OH), hydroxy ligands (OH orH₂O), ether ligands, or halogen ligands. Such complex compounds can alsooccur intermediately during the breakdown in the body, that is, inparticular in an aqueous solution and, if applicable, in that case alsointermediately coordinatively unsaturated.

In the iron(III)-β-ketoamide complex compounds according to theinvention, the coordination number of the iron atoms is generally six(6), with the coordinating atoms generally being arranged octahedrally.

Furthermore, mono- or polynuclear iron(III)-β-ketoamide complexcompounds in which one or more (such as 2, 3 or 4) iron atoms arepresent are also comprised according to the invention. However,mononuclear iron(III)-β-ketoamide complex compounds in which a centraliron atom is present are preferred.

Generally, 1-4 iron atoms and 2-10 ligands can be present in theiron(III)-(1-ketoamide complex compounds. Mononucleariron(III)-β-ketoamide complex compounds with at least one preferablytri-, preferably bidentate β-ketoamide ligand are preferred.

The iron(III)-β-ketoamide complex compounds are generally present inneutral form. However, salt-like iron(III)-β-ketoamide complex compoundsare also included, in which the complex has a positive or negativecharge which is compensated, in particular, by pharmacologicallycompatible, substantially non-coordinating anions (such as, inparticular, halogenides, such as chloride) or cations (such as, inparticular, alkaline or alkaline-earth metal ions).

According to the invention, iron(III) complex compounds are particularlypreferred that contain at least one ligand of the formula (I):

-   -   wherein    -   the arrows respectively represent a coordinate bond to one or        different iron atoms,    -   R₁ is selected from the group consisting of optionally        substituted alkyl, and optionally substituted alkoxycarbonyl,    -   R₂ is selected from the group consisting of hydrogen, optionally        substituted alkyl, halogen and cyano, or    -   R₁ and R₂, together with the carbon atoms to which they are        bonded, form an optionally substituted 5- or 6-membered ring,        which may optionally contain one or more heteroatoms,    -   R₃ and R₄ are the same or different and are respectively        selected from the group consisting of hydrogen, optionally        substituted amino, and optionally substituted alkyl, or    -   R₃ and R₄, together with the nitrogen atom to which they are        bonded, form an optionally substituted 3- to 6-membered ring,        which may optionally contain one or more further heteroatoms,    -   or    -   R₂ and R₃ together form a saturated or unsaturated, optionally        substituted 5- or 6-membered ring while forming a ligand of the        formula (Ia):

-   -   wherein R₁ and R₄ are defined as above,    -   or    -   R₂ and R₃ together form a saturated or unsaturated, optionally        substituted 5- or 6-membered ring, and R₁ and R₂ together form a        saturated or unsaturated, optionally substituted 5- or        6-membered ring, while forming a ligand of the formula (Ib):

-   -   wherein R₄ is defined as above,    -   or pharmaceutically acceptable salts thereof.

Particularly preferred according to the invention are iron(III)-complexcompounds comprising at least one ligand of formula (I):

whereinthe arrows respectively represent a coordinate bond to one or differentiron atoms,R₁ is optionally substituted alkyl,R₂ is selected from the group consisting of hydrogen, optionallysubstituted alkyl, halogen and cyano, orR₁ and R₂, together with the carbon atoms to which they are bonded, forman optionally substituted 5- or 6-membered ring, which may optionallycontain one or more heteroatoms,R₃ and R₄ are the same or different and are respectively selected fromthe group consisting of hydrogen and optionally substituted alkyl, orR₃ and R₄, together with the nitrogen atom to which they are bonded,form an optionally substituted 3- to 6-membered ring, which mayoptionally contain one or more further heteroatoms,or, in another embodiment:R₂ and R₃ together form a saturated or unsaturated, optionallysubstituted 5- or 6-membered ring while forming a ligand of the formula(Ia):

wherein R₁ and R₄ are defined as above,or, in another embodiment:R₂ and R₃ together form a saturated or unsaturated, optionallysubstituted 5- or 6-membered ring, and R₁ and R₂ together form asaturated or unsaturated, optionally substituted 5- or 6-membered ring,while forming a ligand of the formula (Ib):

wherein R₄ is defined as above,or pharmaceutically acceptable salts thereof.

A preferred embodiment of the invention relates to this iron(III)complex compounds, containing at least one ligand of the formula (I):

whereinthe arrows respectively represent a coordinate bond to one or differentiron atoms,R₁ is selected from the group consisting of optionally substitutedalkyl, and optionally substituted alkoxycarbonyl, preferably optionallysubstituted alkyl,R₂ is selected from the group consisting of hydrogen, optionallysubstituted alkyl, halogen and cyano, orR₁ and R₂, together with the carbon atoms to which they are bonded, forman optionally substituted 5- or 6-membered ring, which may optionallycontain one or more heteroatoms,R₃ and R₄ are the same or different and are respectively selected fromthe group consisting of hydrogen, optionally substituted amino, andoptionally substituted alkyl, preferably hydrogen and optionallysubstituted alkyl, orR₃ and R₄, together with the nitrogen atom to which they are bonded,form an optionally substituted 3- to 6-membered ring, which mayoptionally contain one or more further heteroatoms.

Within the overall context of the invention, optionally substitutedalkyl, in particular for the substituents R₁ to R₄, preferably includes:

Straight-chained or branched alkyl with 1 to 8, preferably 1 to 6 carbonatoms, cycloalkyl with 3 to 8, preferably 5 or 6 carbon atoms, or alkylwith 1 to 4 carbon atoms, which is substituted with cycloalkyl, whereinthese alkyl groups can be optionally substituted.

The above-mentioned alkyl groups can optionally carry preferably 1 to 3substituents, respectively.

These substituents are preferably selected from the group consisting of:hydroxy, optionally substituted aryl, in particular as defined below,optionally substituted heteroaryl, in particular as defined below,optionally substituted alkoxy, in particular as defined below,optionally substituted alkoxycarbonyl, in particular as defined below,optionally substituted acyl, in particular as defined below, halogen, inparticular as defined below, optionally substituted amino, in particularas defined below, optionally substituted aminocarbonyl, in particular asdefined below, and cyano.

Iron(III) complex compounds in which R₁, R₂, R₃ and/or R₄ represent arylor heteroaryl-substituted alkyl groups are less preferred according tothe invention.

Halogen includes, here and within the context of the present invention,fluorine, chlorine, bromine and iodine, preferably fluorine or chlorine.

In the above-defined alkyl groups, optionally one or more, morepreferably 1 to 3 carbon atoms can furthermore be replaced withhetero-analogous groups that contain nitrogen, oxygen or sulfur. Thismeans, in particular, that, for example, one or more, preferably 1 to 3,still more preferred one (1) methylene group (—CH₂—) can be replaced inthe alkyl groups by —NH—, —NR₅—, —O— or —S—, wherein R₅ is optionallysubstituted alkyl as defined above, preferably C1-C6 alkyl, such asmethyl or ethyl, optionally substituted with 1 to 3 substituents, suchas fluorine, chlorine, hydroxy, alkoxy.

Examples of alkyl residues having 1 to 8 carbon atoms include: a methylgroup, an ethyl group, an n-propyl group, an i-propyl group, an n-butylgroup, an i-butyl group, a sec-butyl group, a t-butyl group, an n-pentylgroup, an i-pentyl group, a sec-pentyl group, a t-pentyl group, a2-methylbutyl group, an n-hexyl group, a 1-methylpentyl group, a2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a1-ethylbutyl group, a 2-ethylbutyl group, a 3-ethylbutyl group, a1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3-dimethylbutylgroup, a 1-ethyl-1-methylpropyl group, an n-heptyl group, a1-methylhexyl group, a 2-methylhexyl group, a 3-methylhexyl group, a4-methylhexyl group, a 5-methylhexyl group, a 1-ethylpentyl group, a2-ethylpentyl group, a 3-ethylpentyl group, a 4-ethylpentyl group, a1,1-dimethylpentyl group, a 2,2-dimethylpentyl group, a3,3-dimethylpentyl group, a 4,4-dimethylpentyl group, a 1-propylbutylgroup, an n-octyl group, a 1-methylheptyl group, a 2-methylheptyl group,a 3-methylheptyl group, a 4-methylheptyl group, a 5-methylheptyl group,a 6-methylheptyl group, a 1-ethylhexyl group, a 2-ethylhexyl group, a3-ethylhexyl group, a 4-ethylhexyl group, a 5-ethylhexyl group, a1,1-dimethylhexyl group, a 2,2-dimethylhexyl group, a 3,3-dimethylhexylgroup, a 4,4-dimethylhexyl group, a 5,5-dimethylhexyl group, a1-propylpentyl group, a 2-propylpentyl group, etc. Those with 1 to 6carbon atoms are preferred. Methyl, ethyl, n-propyl and n-butyl are mostpreferred.

Examples of alkyl groups produced by replacement with one or morehetero-analogous groups, such as —O—, —S—, —NH— or —N(R₅)— arepreferably such groups in which one or more methylene groups (—CH₂—) arereplaced with —O— while forming an ether group, such as methoxymethyl,ethoxymethyl, 2-methoxyethyl etc. Therefore, the definition of alkylalso includes, for example, alkoxyalkyl groups as defined below, whichare produced from the above-mentioned alkyl groups by replacement of amethylene group with —O—. If, according to the invention, alkoxy groupare additionally permitted as substituents of alkyl, several ethergroups can also be formed in this manner (such as a —CH₂—O—CH₂—OCH₃-group). Thus, according to the invention, polyether groupsare also comprised by the definition of alkyl.

Examples of thio-containing alkyl radicals, especially as R₄ are:

Cycloalkyl groups with 3 to 8 carbon atoms preferably include: acyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexylgroup, a cycloheptyl group, a cyclooctyl group, etc. A cyclopropylgroup, a cyclobutyl group, a cyclopentyl group and a cyclohexyl groupare preferred. The cycloalkyl groups may optionally be substituted,preferably with 1 to 2 substituents such as hydroxyl, such as in thecase of the 4-hydroxycyclohexyl, or C1-C6-alkoxycarbonyl, such as in thecase of the following radicals:

The definition of the optionally substituted alkyl also includes alkylgroups which are substituted by the above mentioned cycloalkyl groups,such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl orcyclohexylmethyl.

Heterocyclic alkyl groups according to the invention are preferablythose formed by the replacement of methylene with hetero-analogousgroups from cycloalkyl, and include, for example, saturated 5 or6-membered heterocyclic residues, which may be attached via a carbonatom or a nitrogen atom, and which preferably may have 1 to 3,preferably 2 heteroatoms, especially O, N, such as tetrahydrofuryl,azetidine-1-yl, substituted azetidinyl, such as 3-hydroxyazetidin-1-yl,pyrrolidinyl, such as pyrrolidin-1-yl, substituted pyrrolidinyl, such as3-hydroxypyrrolidin-1-yl, 2-hydroxypyrrolidin-1-yl2-methoxycarbonylpyrrolidin-1-yl, 2-ethoxycarbonylpyrrolidin-1-yl,2-methoxypyrrolidin-1-yl, 2-ethoxypyrrolidin-1-yl,3-methoxycarbonylpyrrolidin-1-yl, 3-ethoxycarbonylpyrrolidin-1-yl,3-methoxypyrrolidin-1-yl, 3-ethoxypyrrolidine-1-yl, piperidinyl, such aspiperidin-1-yl, piperidin-4-yl, substituted piperidinyl, such as4-methyl-1-piperidyl, 4-hydroxy-1-piperidyl, 4-methoxy-1-piperidyl,4-ethoxy-1-piperidyl, 4-methoxycarbonyl-1-piperidyl,4-ethoxycarbonyl-1-piperidyl, 4-carboxy-1-piperidyl,4-acetyl-1-piperidyl, 4-formyl-1-piperidyl, 1-methyl-4-piperidyl,4-hydroxy-2,2,6,6-tetramethyl-1-piperidyl,4-(dimethylamino)-1-piperidyl, 4-(diethylamino)-1-piperidyl,4-amino-1-piperidyl, 2-(hydroxymethyl)-1-piperidyl,3-(hydroxymethyl)-1-piperidyl, 4-(hydroxymethyl)-1-piperidyl,2-hydroxy-1-piperidyl, 3-hydroxy-1-piperidyl, 4-hydroxy-1-piperidyl,morpholin-4-yl, substituted morpholinyl, such as 2,6-dimethylmorpholin-4-yl, piperazinyl, such as piperazin-1-yl, substitutedpiperazinyl, such as 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl,4-ethoxycarbonylpiperazin-1-yl, 4-methoxycarbonylpiperazin-1-yl, ortetrahydropyranyl, such as tetrahydropyran-4-yl, and which canoptionally be condensated with aromatic rings, and which may optionallybe substituted, such as with 1 to 2 substituents such as hydroxy,halogen, C1-C6-alkyl, etc. The definition of the optionally substitutedalkyl groups thus includes also alkyl groups, which are substituted bythe above-defined heterocyclic groups, such as 3-(1-piperidyl)propyl,3-pyrrolidin-1-ylpropyl, 3-morpholinopropyl, 2-morpholinoethyl,2-tetrahydropyran-4-ylethyl, 3-tetrahydropyran-4-ylpropyl,3-(azetidin-1-yl)propyl etc.

Examples of a linear or branched alkyl group substituted with halogenand having 1 to 8 carbon atoms include, in particular:

a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, achloromethyl group, a dichloromethyl group, a trichloromethyl group, abromomethyl group, a dibromomethyl group, a tribromomethyl group, a1-fluoroethyl group, a 1-chloroethyl group, a 1-bromoethyl group, a2-fluoroethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a1,2-difluoroethyl group, a 1,2-dichloroethyl group, a 1,2-dibromoethylgroup, a 2,2,2-trifluoroethyl group, a heptafluoroethyl group, a1-fluoropropyl group, a 1-chloropropyl group, a 1-bromopropyl group, a2-fluoropropyl group, a 2-chloropropyl group, a 2-bromopropyl group, a3-fluoropropyl group, a 3-chloropropyl group, a 3-bromopropyl group, a1,2-difluoropropyl group, a 1,2-dichloropropyl group, a1,2-dibromopropyl group, a 2,3-difluoropropyl group, a2,3-dichloropropyl group, a 2,3-dibromopropyl group, a3,3,3-trifluoropropyl group, a 2,2,3,3,3-pentafluoropropyl group, a2-fluorobutyl group, a 2-chlorobutyl group, a 2-bromobutyl group, a4-fluorobutyl group, a 4-chlorobutyl group, a 4-bromobutyl group, a4,4,4-trifluorobutyl group, a 2,2,3,3,4,4,4-heptafluorobutyl group, aperfluorobutyl group, a 2-fluoropentyl group, a 2-chloropentyl group, a2-bromopentyl group, a 5-fluoropentyl group, a 5-chloropentyl group, a5-bromopentyl group, a perfluoropentyl group, a 2-fluorohexyl group, a2-chlorohexyl group, a 2-bromohexyl group, a 6-fluorohexyl group, a6-chlorohexyl group, a 6-bromohexyl group, a perfluorohexyl group, a2-fluoroheptyl group, a 2-chloroheptyl group, a 2-bromoheptyl group, a7-fluoroheptyl group, a 7-chloroheptyl group, a 7-bromoheptyl group, aperfluoroheptyl group, etc.

Examples of an alkyl group substituted with hydroxy include theabove-mentioned alkyl residues, which have 1 to 3 hydroxy residues, suchas, for example hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl,4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, etc. and which possiblyalso may have other substituents such as alkoxycarbonyl or may havehetero atoms, such as sulfur, such as for example:

which are also all examples of R₃ and/or R₄.

Optionally substituted aryl preferably includes according to theinvention aromatic hydrocarbon residues with 6 to 14 carbon atoms (withno hetero atom in the aromatic ring system), for example: phenyl,naphthyl, phenanthrenyl and anthracenyl. The aforementioned aromaticgroups optionally can preferably have one or more, preferably one,substituent, in particular halogen, hydroxy, alkyl, alkoxy, in each caseas explained above or below. A preferred aromatic group is phenyl. Apreferred alkyl substituted with an aromatic group (arylalkyl) isbenzyl.

Optionally substituted aryl according to the present invention furtherincludes optionally substituted heteroaryl, that is, heteroaromaticgroups, such as for example: pyridyl, pyridyl-N-oxide, pyrimidyl,pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl,thiazolyl, oxazolyl or isoxazolyl, indolizinyl, indolyl,benzo[b]thienyl, benzo[b]furyl, indazolyl, quinolyl, isoquinolyl,naphthyridinyl, quinazolinyl. 5- or 6-membered aromatic heterocyclessuch as, for example pyridyl, pyridyl-N-oxide, pyrimidyl, pyridazinyl,furyl and thienyl are preferred. The aforementioned heteroaromaticgroups can preferably have one or more, preferably one, substituent, inparticular halogen, hydroxy, alkyl, alkoxy, in each case as explainedabove or below. Preferred examples of an alkyl substituted with aheteroaromatic group (hetarylalkyl) are methyl, ethyl, or propyl, ineach case substituted with a heteroaromatic group, such asthienylmethyl, pyridylmethyl etc.

According to the invention, optionally substituted alkoxy (RO—)includes, for example, linear or branched alkoxy groups with up to 6carbon atoms, such as a methoxy group, an ethoxy group, an n-propyloxygroup, an i-propyloxy group, an n-butyloxy group, an i-butyloxy group, asec-butyloxy group, a t-butyloxy group, an n-pentyloxy group, ani-pentyloxy group, a sec-pentyloxy group, a t-pentyloxy group, a2-methylbutoxy group, an n-hexyloxy group, an i-hexyloxy group, at-hexyloxy group, a sec-hexyloxy group, a 2-methylpentyloxy group, a3-methylpentyloxy group, a 1-ethylbutyloxy group, a 2-ethylbutyloxygroup, a 1,1-dimethylbutyloxy group, a 2,2-dimethylbutyloxy group, a3,3-dimethylbutyloxy group, a 1-ethyl-1-methylpropyloxy group, etc. Amethoxy group, an ethoxy group, an n-propyloxy group, an i-propyloxygroup, an n-butyloxy group, an i-butyloxy group, a sec-butyloxy group, at-butyloxy group, etc., are preferred. The alkoxy groups may optionallybe substituted, such as with the above possible substituents for alkyl.

Methoxy, ethoxy, n-propoxy, n-butoxy, etc. are preferred alkoxy.

Accordingly, optionally substituted alkoxycarbonyl (RO—CO—) groups areformally derived from the above alkyl groups by adding a —OC(O)— residueunder formation of an optionally substituted alkyloxycarbonyl residue.In that regard reference can be made to the definition of theabove-described alkyl groups. As an alternative optionally substitutedalkoxycarbonyl (RO—CO—) groups are derived from the aforementionedalkoxy groups by the addition of a carbonyl group. Methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, n-butoxycarbonyl tert.-butoxycarbonyletc. are preferred alkoxycarbonyl, which may all be substituted as theabove defined alkyl groups.

Optionally substituted amino includes according to the inventionpreferably: amino (—NH₂), optionally substituted mono- or dialkylamino(RHN—, (R)₂N—) for which with regard to the definition of optionallysubstituted alkyl reference can be made to the above definition.Furthermore included are optionally substituted mono- or diarylaminogroups or mixed optionally substituted alkylarylamino groups, for whichas regards the definition of optionally substituted alkyl or arylreference can be made to the above definitions. Such groups include, forexample methylamino, dimethylamino, ethylamino, hydroxyethylamino, suchas 2-hydroxyethylamino, diethylamino, phenylamino, methylphenylaminoetc. Optionally substituted amino further includes an optionallysubstituted cyclic amino, such as optionally substituted 5 or 6-memberedcyclic amino that may contain further hetero atoms such as N, O, S,preferably O. Examples of such cyclic amino groups include theabove-mentioned nitrogen-containing heterocyclic groups bonded through anitrogen atom, such as piperidin-1-yl, 4-hydroxy-piperidin-1-yl,2-(methoxycarbonyl)pyrrolidin-1-yl, pyrrolidin-1-yl, morpholin-4-yl,etc.

Optionally substituted acyl includes, within the scope of the inventionaliphatic and aromatic acyl, wherein aliphatic acyl is, in particular,formyl and optionally substituted alkylcarbonyl, for which with regardto the definition of the optionally substituted alkyl reference can bemade to the foregoing definition of optionally substituted alkyl.Aromatic acyl therefore includes an optionally substituted arylcarbonyl,for which with regard to the definition of the optionally substitutedaryl reference can be made to the foregoing definition of optionallysubstituted aryl. Preferred acyl groups according to the inventioninclude for example: formyl (—C(═O)H), acetyl, propionyl, butanoyl,pentanoyl, hexanoyl, and in each case the isomers thereof, and benzoyl.Substituents of acyl groups include the above mentioned substituents foralkyl and aryl, and accordingly it can be referred to the abovedefinitions.

Optionally substituted aminocarbonyl according to the invention can beformally derived from the above defined optionally substituted amino byadding a carbonyl from ((R)₂N—C(═O)—), and accordingly reference can bemade to the above definition of optionally substituted amino. Examplesinclude, therefore, carbamoyl (H₂NC(═O)—), optionally substituted mono-or dialkylaminocarbonyl (RHNC(═O)—, (R)₂NC(═O)—) wherein reference canbe made to the above definition of optionally substituted alkyl.Furthermore are included are optionally substituted mono- ordiarylaminocarbonyl residues or mixed optionally substitutedalkylarylaminocarbonyl radicals, wherein reference can be made to theabove definitions of optionally substituted alkyl and aryl. Such groupsinclude, for example methylaminocarbonyl, dimethylaminocarbonyl,ethylaminocarbonyl, diethylaminocarbonyl, phenylaminocarbonyl,methylphenylaminocarbonyl to etc.

According to the invention, iron(III) complex compounds are preferredthat contain at least one ligand of the formula (I):

whereinthe arrows respectively represent a coordinate bond to one or differentiron atoms,R₁ is alkyl, which can be optionally substituted with 1 to 3substituents selected from the group consisting of hydroxy, alkoxy, ssdefined above, in particular methoxy, ethoxy, halogen, cyano,alkoxycarbonyl, as defined above, such as especially methoxycarbonyl,ethoxycarbonyl, and aminocarbonyl as defined above, in particularcarbamoyl, dimethylaminocarbonyl, orR₁ is alkoxycarbonyl that can be substituted by 1 to 3 substituentsselected from the group consisting of hydroxy, C1-C6-alkoxy and halogen,in particular methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.,R₂ is selected from the group consisting of

-   -   hydrogen,    -   alkyl, which can be optionally substituted with 1 to 3        substituents selected from the group consisting of hydroxy,        alkoxy, halogen, cyano and alkoxycarbonyl,    -   halogen such as chlorine, fluorine, preferably fluorine and    -   cyano or        R₁ and R₂, together with the carbon atoms to which they are        bonded, form an optionally substituted 5- or 6-membered ring,        such as a cyclopentane ring or a cyclohexane ring which may        optionally also contain one or more heteroatoms, and may have        further substituents such as those mentioned for alkyl,        R₃ and R₄ are the same or different and are respectively        selected from the group consisting of hydrogen and alkyl, which        can be optionally substituted with 1 to 3 substituents selected        from the group consisting of hydroxy, alkoxy, halogen, cyano,        optionally substituted amino and alkoxycarbonyl, and where alkyl        may have one or more hetero atoms selected from —O— or —S—        instead of —CH₂—, and/or        R₃ and R₄ are selected from optionally substituted amino, as        mentioned above, in particular, hydroxyethylamino,        4-morpholinyl, 1-piperidyl, 4-hydroxy-1-piperidyl,        piperazin-1-yl, 4-methyl-1-yl.

In a preferred embodiment, only one of R₃ or R₄ is hydrogen.

Or R₃ and R₄, together with the nitrogen atom to which they are bonded,form an optionally substituted 3- to 6-membered ring, which mayoptionally contain one or more further heteroatoms, such as theabove-mentioned optionally substituted via nitrogen bonded heterocycles.

Or, in another embodiment

R₂ and R₃ form together form a saturated or unsaturated, optionallysubstituted 5- or 6-membered ring while forming a ligand of the formula(Ia):

wherein R₁ and R₄ are defined as above, like for example realized in thefollowing compounds:

where the 5- or 6-membered ring systems may optionally be substituted,as for example by one to three substituents such as oxo, halogen, suchas in the following example:

which carries oxo as a substituent,or, in another embodimentR₂ and R₃ together form a saturated or unsaturated, optionallysubstituted 5- or 6-membered ring, and R₁ and R₂ together form asaturated or unsaturated, optionally substituted 5- or 6-membered ring,while forming a ligand of the formula (Ib):

wherein R₄ is defined as above,or pharmaceutically acceptable salts thereof.

The iron(III) complex compounds of the formula (II) are particularlypreferred:

wherein R₁, R₂, R₃ and R₄ are respectively defined as above orpreferably as below.

In a preferred embodiment of the invention, R₁ is selected from thegroup consisting of:

-   -   C₁₋₆-alkyl, preferably as presented above, optionally        substituted with C1-4 alkoxy, as explained above, or with        dialkylaminocarbonyl, also as explained above,    -   C₃₋₆-cycloalkyl, preferably as presented above,    -   C₃₋₆-cycloalkyl-C₁₋₄-alkyl, preferably as presented above,    -   C₁₋₄-alkoxy-C₁₋₄-alkyl, preferably as presented above,    -   hydroxy-C₁₋₄-alkyl, preferably as presented above, and    -   halogen-C₁₋₄-alkyl, preferably as presented above, or    -   C₁₋₄-alkoxycarbonyl, preferably as described above.

Particularly preferably, R₁ is C₁₋₆-alkyl, preferably as presentedabove, in particular methyl, ethyl, propyl, in particular n-propyl, andbutyl, in particular n-butyl. Most preferably, R₁ is methyl, ethyl andn-butyl which are optionally substituted by C₁₋₆-alkoxy, such as methoxyor by di-C₁₋₆-alkylaminocarbonyl such as dimethylaminocarbonyl, or R₁ isC1-4 alkoxycarbonyl, especially methoxycarbonyl or ethoxycarbonyl.

In a preferred embodiment of the invention, R₂ is selected from thegroup consisting of:

-   -   hydrogen,    -   halogen, preferably as presented above.    -   C₁₋₆-alkyl, preferably as presented above,    -   C₃₋₆-cycloalkyl, preferably as presented above,    -   halogen-C₁₋₄-alkyl, preferably as presented above, and    -   cyano.

Particularly preferably, R₂ is hydrogen, halogen, C₁₋₆-alkyl or Cyano,respectively preferably as presented above, still more preferablyhydrogen, methyl and halogen, in particular chlorine or fluorine, mostpreferably hydrogen or fluorine.

In one embodiment of the invention, R₁ and R₂, together with the carbonatoms to which they are bonded, can form an optionally substituted 5- or6-membered ring, which may optionally contain one or more (such as, inparticular, 2) heteroatoms. In that case, β-ketoamide ligands of thefollowing formula are present:

wherein R₃ and R₄ are as described above or below. However, thisembodiment is less preferred.

In this embodiment, R₁ and R₂ together preferably represent a propylene(—CH₂—CH₂—CH₂—)— or a butylene (—CH₂—CH₂—CH₂—CH₂—)-group, in which onemethylene group (—CH₂—), respectively, can be replaced with —O—, —NH—,or —NR₅—, wherein R₅ is optionally substituted alkyl, and wherein thegroups formed by R₁ and R₂ can furthermore respectively be substitutedby one to three substituents selected from the group consisting ofhydroxy, C₁₋₄-alkoxy, amino and mono- or di-(C₁₋₄-alkyl)amino. Exemplaryligands are the following:

wherein R₃ and R₄ are respectively defined as above and wherein therings may optionally carry 1 or 2 substituents such as oxo, alkyl orhalogen.

In the invention, R₃ and R₄ are the same or different and arerespectively selected from the group consisting of hydrogen, optionallysubstituted amino, and optionally substituted alkyl, preferably fromhydrogen and optionally substituted alkyl, each as defined above.

Or R₃ and R₄, together with the nitrogen atom to which they are bonded,form an optionally substituted 3- to 6-membered ring, which mayoptionally contain one or more further heteroatoms each as definedabove.

Preferably, R₃ and R₄ are the same or different and are respectivelyselected from the group consisting of:

-   -   hydrogen, and    -   substituted or unsubstituted alkyl groups, such as selected        from:    -   C₁₋₆-alkyl, preferably as presented above,    -   Di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl such as dimethyl- or        diethylamino-C₁₋₆-alkyl, preferably as described above,    -   Di(C₁₋₆-alkyl)aminocarbonyl-C₁₋₆-alkyl such as        aminocarbonyl-C₁₋₆-alkyl, or dimethyl- or        diethylaminocarbonyl-C₁₋₆-alkyl, preferably as described above,    -   C₃₋₆-cycloalkyl, preferably as presented above,    -   C₃₋₆-cycloalkyl-C₁₋₄-alkyl, preferably as presented above,    -   C₁-C₄-alkoxy-C₁₋₄-alkyl, preferably as presented above,    -   C₁₋₃-alkoxycarbonyl-C₃₋₆-cycloalkyl, preferably as described        above,    -   C₁₋₃-alkoxycarbonyl-C₁₋₆-alkyl, preferably as presented above,    -   hydroxy-C₁₋₄-alkyl, preferably as presented above, and    -   halogen-C₁₋₄-alkyl, preferably as presented above,    -   where possibly also more that one substituent can be present        simultaneously on the alkyl, such as hydroxy and        C₁₋₃-alkoxycarbonyl, or more hydroxyl groups, such as 2 to 3        hydroxyl groups,    -   C₃₋₆-cycloalkyl also includes C₃₋₆-heterocyclyl, and where        appropriate —CH₂— can be replaced by —S—, in each case as        described above, or        R₃ and R₄ together form an ethylene (—CH₂—CH₂—)—, propylene        (—CH₂—CH₂—CH₂—)—, isopropylene (—CH₂—CH(CH₃)—)—, butylene        (—CH₂—CH₂—CH₂—CH₂—)—, isobutylene-, pentylene        (—CH₂—CH₂—CH₂—CH₂—CH₂—)—, or isopentylene group, in which in        each case one methylene group (—CH₂—), respectively, can be        replaced with —O—, —NH—, or —NR₅—, wherein R₅ is optionally        substituted alkyl, and wherein the groups formed by R₃ and R₄        can furthermore respectively be substituted by one to three        substituents selected from the group consisting of hydroxy,        C₁₋₄-alkoxy, amino (—NH₂) and mono- or di(C₁₋₄-alkyl)amino.        Which means that R₃ and R₄ in this case, form an optionally        substituted nitrogen-containing 5- to 6-membered heterocycle,        such as the above or those indicated below.

Particularly preferably, R₃ and R₄ are the same or different and areselected from

-   -   hydrogen,    -   C₁₋₆-alkyl, preferably as presented above, in particular methyl,        ethyl, propyl, in particular n-propyl, butyl, in particular        n-butyl, pentyl, in particular n-pentyl and hexyl, in particular        n-hexyl, and    -   hydroxy-C₁₋₄-alkyl, preferably as presented above, and        preferably hydroxymethyl, hydroxyethyl,    -   C₁₋₃-alkoxycarbonyl-C₁₋₆-alkyl, preferably as presented above,        and preferably methoxycarbonyl, ethoxycarbonyl,    -   C₁₋₄-alkoxy-C₁₋₄-alkyl, as presented above.

Furthermore, in a preferred embodiment, R₃ and R₄ together form apentylene (—CH₂—CH₂—CH₂—CH₂—CH₂—)— group, in which one methylene group(—CH₂—), respectively, can be replaced with —O—, —NH—, or —NR₅— (asdefined above), and which can be respectively substituted by asubstituent selected from hydroxy, C₁₋₄-alkoxy, amino (—NH₂) and mono-or di(C₁₋₄-alkyl)amino. Examples of groups arising from R₃ and R₄ andthe nitrogen atom to which they are bonded, are, for example theabove-mentioned via nitrogen bound heterocycles, which can optionallyhave 1 to 3, like 1 or 2 hetero atoms such as in particular O, N, suchas azetidin-1-yl, substituted azetidinyl, such as3-hydroxyazetidin-1-yl, pyrrolidinyl, such as pyrrolidin-1-yl,substituted pyrrolidinyl, such as 3-hydroxypyrrolidin-1-yl,2-hydroxypyrrolidin-1-yl, 2-methoxycarbonylpyrrolidin-1-yl,2-ethoxycarbonylpyrrolidin-1-yl, 2-methoxypyrrolidin-1-yl,2-ethoxypyrrolidine-1-yl, 3-methoxycarbonylpyrrolidin-1-yl,3-ethoxycarbonylpyrrolidin-1-yl, 3-methoxypyrrolidin-1-yl,3-ethoxypyrrolidin-1-yl, piperidinyl, such as piperidin-1-yl,substituted piperidinyl such as 4-methyl-1-piperidyl,4-hydroxy-1-piperidyl, 4-methoxy-1-piperidyl, 4-ethoxy-1-piperidyl,4-methoxycarbonyl-1-piperidyl, 4-ethoxycarbonyl-1-piperidyl,4-carboxy-1-piperidyl, 4-acetyl-1-piperidyl, 4-formyl-1-piperidyl,4-hydroxy-2,2,6,6-tetramethyl-1-piperidyl,4-(dimethylamino)-1-piperidyl, 4-(diethylamino)-1-piperidyl,4-amino-1-piperidyl, 2-(hydroxymethyl)-1-piperidyl,3-(hydroxymethyl)-1-piperidyl, 4-(hydroxymethyl)-1-piperidyl,2-hydroxy-1-piperidyl, 3-hydroxy-1-piperidyl, morpholino-4-yl,substituted morpholinyl, such as 2,6-dimethyl morpholine-4-yl,piperazinyl, such as piperazin-1-yl, substituted piperazinyl, such as4-methyl-piperazin-1-yl, 4-ethylpiperazin-1-yl,4-ethoxycarbonylpiperazin-1-yl, 4-methoxycarbonylpiperazin-1-yl.

Particularly preferred are piperidin-1-yl, piperazin-1-yl,morpholin-4-yl which may optionally be substituted, such as by hydroxyl,such as 4-hydroxy-piperidin-1-yl. Even more preferred are4-hydroxy-piperidin-1-yl and piperidin-1-yl.

In another less preferred embodiment of the invention, R₂ and R₃together form a saturated or unsaturated, optionally substituted 5- or6-membered ring while forming a β-ketoamide of the formula (Ia):

wherein R₁ and R₄ are defined as above. Examples for such ligands arecompounds in which R₂ and R₃ together form an ethylene (—CH₂—CH₂—)— orpropylene (—CH₂—CH₂—CH₂—)— group:

Ligands of this type are described, for example, in Korte et al.,Chemische Berichte, 95, 2424 and Wamhoff et al., Liebigs Ann. Chem. 715,23-34 (1968).

In another also less preferred embodiment of the invention, R₂ and R₃together form a saturated or unsaturated, optionally substituted 5- or6-membered ring, and R₁ and R₂ together form a saturated or unsaturated,optionally substituted 5- or 6-membered ring, while forming aβ-ketoamide of the formula (Ib):

wherein R₄ is defined as above.

Examples of such ligands include:

It is clear to the person skilled in the art that the ligands accordingto the invention

arise from the corresponding β-ketoamide compounds:

in which there is a keto-enol tautomerism, as is known:

The mesomeric forms A and C are analytically indistinguishable. In thecontext of the present invention in each case, all forms are included,but in the context of the present invention the ligand in general, isonly drawn in the keto form.

Formally, the ligand formally arises from the corresponding β-ketoamidecompounds by abstraction of a proton.

formally therefore carries a uninegative charge. Also for the ironcomplex compounds in the context of the present invention always onlyone of the localized resonance formulas is depicted:

although due to the lower electron density at the amidic oxygen atom, isto be expected that the resonance formula C prevails. As explainedabove, an analytical distinction of the resonance formulas A and C isnot possible.

Examples of the β-ketoamide ligands used in the present invention areshown below:

The iron(III)-β-ketoamide complex compounds, in particular of thegeneral formula (II), can be present in the form or various isomers.Isomeric forms include, for example, regioisomers which differ in theposition of the ligands relative to one another, including so-calledoptical isomers that have an image/mirror image relationship to oneanother. If asymmetric carbon atoms are present, the ligands can bepresent in the form or optical isomers which have a image/mirror imagerelationship to one another, and include pure enantiomers, mixtures ofthe enantiomers, in particular racemates. Enantiomerically pure ligandscan be obtained, as is known to the person skilled in the art, byoptical resolution methods, such as reaction with chiral reagents toform diastereomers, separation of the diastereomers and release of theenantiomers.

Furthermore, in particular the following are preferred embodiments ofthe invention:

(In the present invention, the digits 1-6 in “1-6C” or “C₁₋₆”, or “1-4”in “1-4C” or “C₁₋₄” etc. in each case signify the number of the carbonatoms of the subsequent hydrocarbon group designations).

R₁ is selected from the group consisting of:

-   -   1-6C-alkyl, (i.e. alkyl with 1 to 6 carbon atoms),    -   3-6C-cycloalkyl,    -   3-6C-cycloalkyl-1-4C-alkyl,    -   1-4C-alkoxy-1-4C-alkyl,    -   hydroxy-1-4C-alkyl,    -   fluoro-1-4C-alkyl;

R₂ is selected from the group consisting of:

-   -   H,    -   1-6C-alkyl,    -   3-6C-cycloalkyl,    -   fluoro-1-4C-alkyl,    -   halogen,    -   cyano;        or R₁ and R₂ together form a propylene (—CH₂—CH₂—CH₂), butylene        (—CH₂—CH₂—CH₂—CH₂—), azabutylene or oxabutylene group;

R₃ and R₄ are the same or different and are respectively selected fromthe group consisting of:

-   -   H,    -   1-6C-alkyl,    -   3-6C-cycloalkyl,    -   3-6C-cycloalkyl-1-4C-alkyl,    -   1-4C-alkoxy-1-4C-alkyl,    -   1-3C-alkoxy-carbonyl-1-6C-alkyl,    -   hydroxy-1-4C-alkyl,    -   fluoro-1-4C-alkyl;        or R₃ and R₄ together form an ethylene (—CH₂—CH₂ ⁺, propylene        (—CH₂—CH₂—CH₂ ⁺, hydroxypropylene, preferably        2-hydroxypropylene, 3-methylpropylene, butylene        (—CH₂—CH₂—CH₂—CH₂—), 2-hydroxybutylene, 2-methoxybutylene,        isobutylene, pentylene (—CH₂—CH₂—CH₂—CH₂—CH₂—),        hydroxypentylene, preferably 3-hydroxypentylene,        methoxypentylene, preferably 3-methoxypentylene,        ethoxypentylene, preferably 3-ethoxypentylene, propoxypentylene,        preferably 3-propoxypentylene, isopropoxypentylene, preferably        3-isopropoxypentylene, cyclopropoxypentylene, preferably        3-cyclopropoxypentylene, azapentylene in particular        —CH₂—CH₂—NH—CH₂—CH₂—, or an oxapentylene group, in particular        —CH₂—CH₂—O—CH₂—CH₂—        or pharmaceutically acceptable salts thereof.

Preferably, the aforementioned substituent groups are defined asfollows:

1-6C-alkyl preferably includes straight-chained or branched alkyl groupswith 1 to 6 carbon atoms. Examples therefor can be methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyln-pentyl, iso-pentyl, neo-pentyl, n-hexyl, iso-hexyl and neo-hexyl.3-6C-Cycloalkyl preferably includes cycloalkyl 1 to 6 carbon atoms, suchas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.3-6C-cycloalkyl-1-4C-alkyl preferably includes a 1-6C-alkyl groupdescribed above, substituted with a 3-6C-cycloalkyl group describedabove. Examples therefor can be a cyclopropylmethyl, cyclopentylmethyland cyclohexylmethyl group.1-3C-alkoxy-carbonyl-1-6C-alkyl, preferably includes a 1-6C-alkyl groupdescribed above, which is linked to a carbonyl group which is presentwith a 1-3C alkoxy group as a carboxylic acid ester. Examples thereforcan be methoxycarbonylmethyl, ethoxycarbonylmethyl,methoxycarbonylethyl, ethoxycarbonylethyl and isopropoxycarbonylmethyl.1-4C-alkoxy preferably includes a 1-4C-alkoxy group, in which an oxygenatom is connected to a straight or branched alkyl chain with 1-4 carbonatoms. Examples of this group can be methoxy, ethoxy, propoxy andisobutoxy.1-4C-alkoxy-1-4C-alkyl preferably includes a 1-4C-alkoxy group describedabove, which is substituted with a 1-4C-alkyl group described above.Examples of this group can be methoxyethyl, ethoxypropyl, methoxypropyl,isobutoxymethyl.Hydroxy-1-4C-alkyl includes a 1-4C-alkyl group described above, which issubstituted with a hydroxy group. Examples therefor can be hydroxyethyl,hydroxybutyl and hydroxyisopropyl.Fluoro-1-4C-alkyl includes a 1-4C-alkyl group described above, which issubstituted with one to three fluorine atoms. Examples therefor can bytrifluoromethyl and trifluoreethyl.Halogen signifies F, Cl, Br, I.

The groups and residues can also contain chiral centers. In that case,all possible entantiomer mixtures and the pure enantiomers are thenincluded.

Particularly preferably:

R₁ is selected from the group consisting of:

-   -   1-6C-alkyl,    -   1-4C-alkoxy-1-4C-alkyl,    -   hydroxy-1-4C-alkyl;        R₂ is selected from the group consisting of:    -   H,    -   1-6C-alkyl; and        R₃ and R₄ are the same or different and are respectively        selected from the group consisting of:    -   H,    -   1-6C-alkyl,    -   1-4C-alkoxy-1-4C-alkyl,    -   1-3C-alkoxy-carbonyl-1-6C-alkyl,    -   hydroxy-1-4C-alkyl;        or R₃ and R₄ together form a butylene (—CH₂—CH₂—CH₂—CH₂—)—,        pentylene (—CH₂—CH₂—CH₂—CH₂—CH₂—), hydroxypentylene,        azapentylene or oxapentylene group.

Particularly preferably:

R₁ is selected from the group consisting of:

-   -   1-6-C-alkyl;        R₂ is selected from the group consisting of:    -   H,    -   1-6C-alkyl;        and        R₃ and R₄ are the same or different and are respectively        selected from the group consisting of:    -   H,    -   1-6C-alkyl,    -   1-4C-alkoxy-1-4C-alkyl,    -   1-3C-alkoxy-carbonyl-1-6C-alkyl,    -   hydroxy-1-4C-alkyl;        or R₃ and R₄ together form a pentylene (—CH₂—CH₂—CH₂—CH₂—CH₂—),        hydroxypentylen, preferably 3-hydroxypentylene or oxapentylene        group, as described above.

Particularly preferred complex compounds of the general formula (II) aredescribed in the examples.

The invention further relates to a method for the preparation of theiron(III) complex compounds according to the invention which comprisesthe reaction of a β-ketoamide with an iron(III) salt.

β-ketoamide include, in particular, those of the formula (III):

wherein R₁ to R₄ are defined as above.

Examples of suitable iron(III) salts include: iron(III) chloride,iron(III) acetate, iron(III) sulfate, iron(III) nitrate and iron(III)acetylacetonate, among which iron(III) chloride is preferred.

Another preferred method is shown in the following scheme:

wherein R₁ to R₄ are defined as above, X is an anion such as halogenide,such as chloride, a carboxylate, such as acetate, sulfate, nitrate andacetylacetonate and base is a common organic or inorganic base.

In the method according to the invention, preferably 3-5 eq ligand(III), using suitable iron(III) salts (IV) (in this case Fe(III)chloride, Fe(III) acetate, Fe(III) sulfate and Fe(III) acetylacetonateare particularly suitable), are reacted under standard conditions toform the corresponding complexes of the general formula (II). In thiscase, the synthesis is carried out under the pH conditions optimal forcomplex formation. The optimum pH value is set by adding a base (V); inthis case, the use of sodium carbonate, sodium hydrogencarbonate, sodiummethanolate, potassium carbonate, potassium hydrogencarbonate orpotassium methanolate is particularly suitable.

The ligands (III) required for the preparation of the complexes areeither commercially available or were prepared according to thefollowing synthesis method. For this purpose, two different synthesisprocesses were used. For ligands of the general formula R₁=methyl, R₂═Hthe commercially available diketone (3) was reacted under standardconditions with the corresponding amine (4) to form the ligand of thegeneral formula (III).

For the other ligands of the general formula (III), the appropriateketoester (5) was reacted under standard conditions with thecorresponding amine (6).

wherein R₁ to R₄ are respectively defined as above.

Pharmaceutically acceptable salts of the compounds according to theinvention in which the iron(III) complex formally carries a positivecharge include, for example, salts with suitable anions, such ascarboxylates, sulfonates, sulfates, chlorides, bromides, iodides,phosphates, tartates, methanesulfonates, hydroxethanesulfonates,glycinates, maleates, propionates, fumarates, tulouenesulfonates,benzene sulfonates, trifluoroacetates, naphthalenedisulfonates-1,5,salicylates, benzoates, lactates, salts of malic acid, salts of3-hydroxy-2-naphthoic acid-2, citrates and acetates.

Pharmaceutically acceptable salts of the compounds according to theinvention in which the iron(III) complex formally carries a negativecharge include, for example, salts with suitable pharmaceuticallyacceptable bases, such as, for example, salts with alkaline oralkaline-earth hydroxides, such as NaOH, KOH, Ca(OH)₂, Mg(OH)₂ etc.,amine compounds such as ethylamine, diethylamine, triethylamine,ethyldiisopropylamine, ethanolamine, diethanolamine, triethanolamine,methylglucamine, dicyclohexylamine, dimethylaminoethanol, procaine,dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine,N-methylpiperidin, 2-amino-2-methyl-propanol-(1),2-amino-2-methyl-propandiol-(1,3),2-amino-2-hydroxyl-methyl-propandiol-(1,3) (TRIS) etc.

The water-solubility or the solubility in physiological saline solutionand thus, optionally, also the efficacy of the compounds according tothe invention can be significantly influenced by salt formation ingeneral, specifically by the choice of the counterion.

Preferably, the compounds according to the invention constitute neutralcomplex compounds.

Advantageous Pharmacological Effects:

Surprisingly, the inventors found that the iron(III) β-ketoamide complexcompounds which are the subject matter of the present invention andwhich are represented, in particular, by the general structural formula(II), are stable bioavailable iron complexes and suitable for use as amedicament for the treatment and prophylaxis of iron deficiency symptomsand iron deficiency anemias the symptoms accompanying them.

The medicaments containing the compounds according to the invention aresuitable for use in human and veterinary medicine.

The compounds according to the invention are thus also suitable forpreparing a medicament for the treatment of patients suffering fromsymptoms of an iron deficiency anemia, such as, for example: fatigue,listlessness, lack of concentration, low cognitive efficiency,difficulties in finding the right words, forgetfulness, unnaturalpallor, irritability, acceleration of heart rate (tachycardia), sore orswollen tongue, enlarged spleen, desire for strange foods (pica),headaches, lack of appetite, increased susceptibility to infections ordepressive moods.

The iron(III) complex compounds according to the invention arefurthermore suitable for the treatment of iron deficiency anemia inpregnant women, latent iron deficiency anemia in children andadolescents, iron deficiency anemia caused by gastrointestinalabnormalities, iron deficiency anemia due to blood loss, such asgastrointestinal hemorrhage (e.g. due to ulcers, carcinoma, hemorrhoids,inflammatory disorders, taking of acetylsalicylic acid), iron deficiencyanemia caused by menstruation, iron deficiency anemia caused byinjuries, iron deficiency anemia due to sprue, iron deficiency anemiadue to reduced dietary iron uptake, in particular in selectively eatingchildren and adolescents, immunodeficiency caused by iron deficiencyanemia, brain function impairment caused by iron deficiency anemias,restless leg syndrome caused by iron deficiency anemias, iron deficiencyanemias in the case of cancer, iron deficiency anemias caused bychemotherapies, iron deficiency anemias triggered by inflammation (AI),iron deficiency anemias in the case of congestive cardiac insufficiency(CHF; congestive heart failure), iron deficiency anemias in the case ofchronic renal insufficiency stage 3-5 (CDK 3-5; chronic kidney diseasesstage 3-5), iron deficiency anemias triggered by chronic inflammation(ACD), iron deficiency anemias in the case of rheumatoid arthritis (RA),iron deficiency anemias in the case of systemic lupus erythematosus(SLE) and iron deficiency anemias in the case of inflammatory boweldiseases (IBD).

Administration can take place over a period of several months until theiron status is improved, which is reflected, for example, by thehemoglobin level, transferrin saturation and the serum ferritin level ofthe patients, or until the desired improvement of the state of healthaffected by iron deficiency anemia.

The preparation according to the invention can be taken by children,adolescents and adults.

The applied compounds according to the invention can in this case beadministered both orally as well as parentally. Oral administration ispreferred.

The compounds according to the invention and the aforementionedcombinations of the compounds according to the invention with otheractive substances or medicines can thus be used, in particular, for thepreparation of medicaments for the treatment of iron deficiency anemia,such as iron deficiency anemia in pregnant women, latent iron deficiencyanemia in children and adolescents, iron deficiency anemia caused bygastrointestinal abnormalities, iron deficiency anemia due to bloodloss, such as gastrointestinal hemorrhage (e.g. due to ulcers,carcinoma, hemorrhoids, inflammatory disorders, taking ofacetylsalicylic acid), menstruation, injuries, iron deficiency anemiadue to sprue, iron deficiency anemia due to reduced dietary iron uptake,in particular in selectively eating children and adolescents,immunodeficiency caused by iron deficiency anemia, brain functionimpairment caused by iron deficiency anemia, restless leg syndrome.

The application according to the invention leads to an improvement ofthe iron, hemoglobin, ferritin and transferrin levels, which, inparticular in children and adolescents, but also in adults, isaccompanied by an improvement in short-term memory tests (STM),long-term memory tests (LTM), Ravens' progressive matrices test, in theWechsler adult intelligence scale (WAIS) and/or in the emotionalcoefficient (Baron EQ-i, YV test, youth version), or to an improvementof the neutrophile level, the antibody levels and/or lymphocytefunction.

Furthermore, the present invention relates to pharmaceuticalcompositions comprising one or more of the compounds according to theinvention, in particular according to the formula (II), as well asoptionally one or more further pharmaceutically effective compounds, aswell as optionally one or more pharmacologically acceptable carriersand/or auxiliary substances and/or solvents.

These are common pharmaceutical carriers, auxiliary substances orsolvents. The above-mentioned pharmaceutical compositions are suitable,for example, for intravenous, intraperitoneal, intramuscular,intravaginal, intrabuccal, percutaneous, subcutaneous, mucocutaneous,oral, rectal, transdermal, topical, intradermal, intragasteral orintracutaneous application and are provided, for example, in the form ofpills, tablets, enteric-coated tablets, film tablets, layer tablets,sustained release formulations for oral, subcutaneous or cutaneousadministration (in particular as a plaster), depot formulations,dragees, suppositories, gels, salves, syrup, granulates, suppositories,emulsions, dispersions, microcapsules, microformulations,nanoformulations, liposomal formulations, capsules, enteric-coatedcapsules, powders, inhalation powders, microcrystalline formulations,inhalation sprays, epipastics, drops, nose drops, nose sprays, aerosols,ampoules, solutions, juices, suspensions, infusion solutions orinjection solutions etc.

Preferably, the compounds according to the invention as well aspharmaceutical compositions containing such compounds are appliedorally, although other forms, such as parentally, in particularintravenously, are also possible.

For this purpose, the compounds according to the invention arepreferably provided in pharmaceutical compositions in the form of pills,tablets, enteric-coated tablets, film tablets, layer tablets, sustainedrelease formulations for oral administration, depot formulations,dragees, granulates, emulsions, dispersions, microcapsules,microformulations, nanoformulations, liposomal formulations, capsules,enteric-coated capsules, powders, microcrystalline formulations,epipastics, drops, ampoules, solutions, suspensions, infusion solutionsor injection solutions.

The compounds according to the invention can be administered inpharmaceutical compositions which may contain various organic orinorganic carrier and/or auxiliary materials as they are customarilyused for pharmaceutical purposes, in particular for solid medicamentformulations, such as, for example, excipients (such as saccharose,starch, mannitol, sorbitol, lactose, glucose, cellulose, talcum, calciumphosphate, calcium carbonate), binding agents (such as cellulose,methylcellulose, hydroxypropylcellulose, polypropyl pyrrolidone,gelatine, gum arabic, polyethylene glycol, saccharose, starch),disintegrating agents (such as starch, hydrolyzed starch,carboxymethylcellulose, calcium salt of carboxymethylcellulose,hydroxypropyl starch, sodium glycol starch, sodium bicarbonate, calciumphosphate, calcium citrate), lubricants (such as magnesium stearate,talcum, sodium laurylsulfate), a flavorant (such as citric acid,menthol, glycin, orange powder), preserving agents (such as sodiumbenzoate, sodium bisulfite, methylparaben, proylparaben), stabilizers(such as citric acid, sodium citrate, acetic acid and multicarboxylicacids from the titriplex series, such as, for example,diethylenetriaminepentaacetic acid (DTPA), suspending agents (such asmethycellulose, polyvinyl pyrrolidone, aluminum stearate), dispersingagents, diluting agents (such as water, organic solvents), beeswax,cocoa butter, polyethylene glycol, white petrolatum, etc.

Liquid medicament formulations, such as solvents, suspensions and gelsusually contain a liquid carrier, such as water and/or pharmaceuticallyacceptable organic solvents. Furthermore, such liquid formulations canalso contain pH-adjusting agents, emulsifiers or dispersing agents,buffering agents, preserving agents, wetting agents, gelatinizing agents(for example methylcellulose), dyes and/or flavoring agents. Thecompositions may be isotonic, that is, they can have the same osmoticpressure as blood. The isotonicity of the composition can be adjusted byusing sodium chloride and other pharmaceutically acceptable agents, suchas, for example, dextrose, maltose, boric acid, sodium tartrate,propylene glycol and other inorganic or organic soluble substances. Theviscosity of the liquid compositions can be adjusted by means of apharmaceutically acceptable thickening agent, such as methylcellulose.Other suitable thickening agents include, for example, xanthan gum,carboxymethylcellulose, hydroxypropylcellulose, carbomer and the like.The preferred concentration of the thickening agent will depend on theagent selected. Pharmaceutically acceptable preserving agents can beused in order to increase the storage life of the liquid composition.Benzyl alcohol can be suitable, even though a plurality of preservingagents including, for example, paraben, thimerosal, chlorobutanol andbenzalkonium chloride can also be used.

The active substance can be administered, for example, with a unit doseof 0.001 mg/kg to 500 mg/kg body weight, for example 1 to 4 times a day.However, the dose can be increased or reduced depending on the age,weight, condition of the patient, severity of the disease or type ofadministration.

EXAMPLES

The invention is illustrated in more detail by the following examples.The examples merely constitute exemplifications, and the person skilledin the art is capable of extending the specific examples to othercompounds claimed. The designation of the names of the examples weredefined and determined using the computer program ACD/Name Version 12.

Starting Compounds:

The starting compounds used in the examples were obtained as follows.

A. N,N-diethyl-3-oxobutaneamide

Commercially available: Fluka 00405

B. N,N-diethyl-3-oxobutaneamide

Commercially available: Aldrich 165093

C. N,N-dimethyl-3-oxobutaneamide

Commercially available: Aldrich 407054

D. N-methyl-3-oxobutaneamide

Commercially available: Acros 25544

E. 2-chloro-N-methyl-3-oxobutaneamide

Commercially available: Aurora Fine Chemicals Ltd. Kafd-00164

F. 1-(piperidin-1-yl)-butane-1,3-dione

A solution of 25 g (0.294 mol) piperidin in 100 mltert.-butyl-methylether was added dropwise to a solution of 26.25 g(0.310 mol) diketene in 200 ml tert.-butyl-methylether at −5 to 0° C.After stirring for 1 hour at −1° C., no starting material was detectedanymore by thin-layer chromatography. The reaction mixture was spun offand the residue was distilled under vacuum. 49.55 g of product wasobtained as a slightly yellow liquid.

IR (in substance, cm⁻¹): 3001, 2936, 2856, 1719, 1631, 1584, 1486, 1441,1389, 1355, 1302, 1255, 1219, 1159, 1137.

Elemental analysis: C, 63.51; H, 8.94; N, 8.36.

LC-MS: 170 (M+H), 192 (M+Na)

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=35 (4H), 3.3 (2H), 2.2 (3H), 1.6 (2H),1.5 (4H).

G. N,N-bis-(2-hydroxyethyl)-3-oxobutaneamide

A solution of 52.53 g (0.50 mol) diethanolamine in 100 ml MeOH was addeddropwise to a solution of 40.00 g (0.48) diketene in 100 ml MeOH at 0°C. After stirring for 1 hour at 0° C., no starting material was detectedanymore by thin-layer chromatography. The reaction mixture was spun offand the residue was purified by means of column chromatography. 81.32 gof product was obtained as a slightly yellow oil.

IR (in substance, cm⁻¹): 3381, 2941, 2885, 1718, 1626, 1481, 1432, 1361,1312, 1212, 1053.

Elemental analysis: C, 50.62; H, 8.05; N, 7.28.

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=2.2 (3H), 3.5 (4H), 3.7 (6H), 4.15(1H), 4.35 (1H).

H. N-butyl-N-methyl-3-oxobutaneamide

14.1 ml (0.12 mol) N-n-butylmethylamine was added dropwise to a solutionof 10.00 g (0.12 mol) diketene in 500 ml MeOH at 0° C. After stirringfor 6 hours at 0° C., no starting material was detected anymore bythin-layer chromatography. The reaction mixture was spun off and theresidue was purified by means of column chromatography. 11.61 g ofproduct was obtained as a slightly yellow oil.

IR (in Substance, cm⁻¹): 2958, 2932, 2873, 1721, 1635, 1593, 1493, 1381,1358, 1307, 1228, 1209, 1144.

LC-MS: 172 (M+H).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=0.9 (3H), 1.3 (2H), 1.5 (2H), 1.9 (1H),2.2 (2H), 2.9 (3H), 3.2 (1H), 3.3 (1H), 3.5 (1H).

I. 1-(4-hydroxypiperidin-1-yl)-butane-1,3-dione

A solution of 25.30 g (0.25 mol) 4-hydroxy-piperidin in 50 ml MeOH wasadded dropwise to a solution of 20.00 g (0.24) diketene in 50 ml MeOH at0° C. After stirring for 1 hour at 0° C., no starting material wasdetected anymore by thin-layer chromatography. The reaction mixture wasspun off and the residue was purified by means of column chromatography.42.54 g (96% yield) of a slightly yellow oil was obtained.

IR (in substance, cm⁻¹): 3401, 2928, 2869, 1717, 1617, 1448, 1360, 1307,1268, 1206, 1158, 1074, 1026.

CHN elemental analysis: C, 57.98; H, 8.69; N, 7.32.

LC-MS: 186 (M+H).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=1.5 (2H), 1.8 (2H), 2.2 (3H), 3.2 (2H),3.6 (3H), 3.9 (2H).

J. 3-oxo-N,N-dipropylbutaneamide

A solution of 27.80 g (0.28 mol) N,N-di-n-propylamine was added dropwiseto a solution of 20.00 g (0.24) diketene in 100 ml MeOH at 0° C. Afterstirring for 3 hours at 0° C., no starting material was detected anymoreby thin-layer chromatography. The reaction mixture was spun off and theresidue was purified by means of column chromatography. 38.05 g ofproduct was obtained as a slightly yellow oil.

IR (in substance, cm⁻¹): 2964, 2934, 2876, 1721, 1634, 1589, 1490, 1456,1430, 1392, 1381, 1359, 1301, 12444, 1101.

Elemental analysis: C, 64.28; H, 10.17; N, 7.36.

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=0.9 (6H), 1.6 (4H), 1.9 (1H), 2.3 (2H),3.1 (2H), 3.3 (2H), 3.5 (2H).

K. N-hexyl-3-oxobutaneamide

A solution of 27.83 g (0.28 mol) N-n-hexylamine was added dropwise to asolution of 20.00 g (0.24) diketene in 100 ml MeOH at 0° C. Afterstirring for 4 hours at 0° C., no starting material was detected anymoreby thin-layer chromatography. The reaction mixture was spun off, and theobtained solid was taken up in 200 ml n-hexane, filtrated off and driedovernight under vacuum. 22.53 g of product was obtained as a whitesolid.

IR (in substance, cm⁻¹): 3272, 3098, 2956, 2921, 2872, 2853, 1728, 1709,1644, 1563, 1467, 1419, 1363, 1347, 1336, 1190, 1167.

Elemental analysis: C, 64.85; H, 10.28; N, 7.62.

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=0.9 (3H), 1.3 (6H), 1.5 (2H), 2.2 (3H),3.2 (2H), 3.4 (2H), 6.9 (1H).

L. Ethyl-N-(3-oxobutanoyl)glycinate (3-oxo-butyrylamino)ethyl acetate)

A solution of 20.00 g (0.24 mol) diketene in 250 ml toluene was addeddropwise at 0° C. to a solution of 33.21 g (0.24 mol) glycine ethylester hydrochloride (amino acetic ester hydrochloride). 40.00 g (0.48mol) NaHCO₃ were then added and the reaction mixture was stirred furtherat room temperature overnight. Since no starting material could bedetected anymore by thin-layer chromatography, the reaction mixture wasspun off, and the obtained solid was taken up in 100 ml diethylether,stirred for a short period of time, filtrated off and dried overnightunder vacuum. 40.00 g of product was obtained as a white solid.

IR (in substance, cm⁻¹): 3346, 1750, 1708, 1669, 1538, 1399, 1360, 1320,1278, 1198, 1165, 1024.

Elemental analysis: C, 51.57; H, 7.05; N, 7.55.

LC-MS: 210 (M+Na), 188 (M+H).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=1.2 (3H), 2.2 (3H), 3.4 (2H), 4.0 (2H),4.2 (2H), 7.4 (1H).

M. 3-oxoheptaneamide

0.4 mol (63.7 ml) 3-oxo-heptanoic acid methylester and 400 ml 7 Nammonia solution was stirred for three hours at 100° C. in a pressurereactor. After cooling off, the solvents were distilled off on arotavap, the raw products were taken up in 200 ml water and 40 mlethanol and set to about pH 3 with 40 ml 32% HCl. The reaction mixturewas heated to 90° C. for 4 hours and then again concentrated to drynessin the rotavap, taken up in 600 ml dichloromethane and washed 3 timeswith 100 ml water. The organic phase was distilled off and the rawproduct recrystallized from 100 ml toluene. The product was filtratedoff and dried in a vacuum drying cabinet at 50° C. 3.5 g of the titlecompound was obtained.

IR (in substance, cm⁻¹): 3368, 3178, 2956, 2932, 2872, 1703, 1651, 1619,1466, 1439, 1408, 1376, 1345, 1306, 1221, 1183, 1125, 1058, 716, 663.

Elemental analysis: C, 58.38; H, 9.12; N, 9.90.

LC-MS: 144 (M+H).

¹H-NMR (DMSO-d₆, 400 MHz): δ [ppm]=14.5 (s, 1H), 7.45 (s, 1H), 7.01 (s,1H), 4.92 (s, 1H), 2.06 (t, 2H), 1.47-1.38 (m, 3H), 1.31-1.18 (m, 2H),0.88-0.81 (m, 3H); keto tautomer (86%), δ=7.45 (s, 1H), 7.01 (s, 1H),3.23 (s, 2H), 2.49 (t, 2H), 1.47-1.38 (m, 2H), 1.31-1.18 (m, 2H),0.88-0.81 (m, 3H).

N. N-methyl-3-oxoheptaneamide

0.378 mol (60.2 ml) 3-oxo-heptanoic acid methylester, 400 ml 33%methylamine solution in ethanol and 40 ml water were stirred for 48hours at 80° C. in a round-bottomed flask with a reflux condenser. Aftercooling off, the solvents were distilled off on a rotavap, the rawproducts were taken up in 200 ml water and 40 ml ethanol and set toabout pH 3 with 40 ml 32% HCl. The reaction mixture was heated to 90° C.for 24 hours and then again concentrated to dryness in the rotavap. Theraw product heated with 150 ml to reflux, filtrated hot and the filtratewas left to cool off. The product was filtrated off and dried in avacuum drying cabinet at 50° C. 5.9 g of the title compound wasobtained.

IR (in substance, cm⁻¹): 3368, 3178, 2956, 2932, 2872, 1703, 1651, 1619,1466, 1439, 1408, 1376, 1345, 1306, 1221, 1183, 1125, 1058, 716, 663.

Elemental analysis: C, 60.22; H, 9.69; N, 8.75.

¹H-NMR (DMSO-d₆, 400 MHz): δ [ppm]=keto tautomer (ca. 90%), enoltautomer*(ca. 10%), =8.21*/7.81*(m, 1H), 7.94 (s, 1H), 6.12*/4.91*(s,1H), 3.25 (s, 2H), 2.69*/2.61*(d, 3H), 2.57 (d, 3H), 2.50-2.46 (m, 2H),2.06*(t, 2H), 1.45-1.38 (m, 2H), 1.31-1.18 (m, 2H), 0.88-0.81 (m, 3H)

(*enol tautomer probably present as E-Z isomer of the amide bond)

O. N,N-dimethyl-3-oxoheptaneamide

0.632 mol (100 ml) methyl-3-oxoheptanoate (3-oxo-heptanoic acidmethylester) and 227 ml 33% dimethylamine solution in ethanol (approx.1.26 mol dimethylamine) was stirred for 4 hours at 110° C. in a pressurereactor. After cooling off, the solvents were distilled off on arotavap, the raw product was taken up in 40 ml water, 30 ml 32% HCl and40 ml ethanol and stirred for 24 hours at 100° C. The mixture was againconcentrated to dryness by evaporation, taken up again in 300 ml aceticester and filtrated, the solvents were then distilled off on therotavap. 26 g of raw product was purified over 500 g silica gel 60(mobile solvent: acetic ester:hexane 1:1, flow 50 ml/min, fraction size:100 ml, product: fractions 20-35), the product was obtained as a mobileoil. 17.8 g of the title compound was obtained.

IR (in substance, cm⁻¹): 2957, 2932, 2873, 1717, 1639, 1597, 1501, 1465,1396, 1366, 1302, 1262, 1197, 1142, 1058, 933, 776, 726, 692, 645, 612.

Elemental analysis: C, 62.12; H, 9.965; N, 8.17.

¹H-NMR (DMSO-d₅, 400 MHz): δ [ppm]=enol tautomer (28%), δ=15.1 (s, 1H),5.32 (s, 1H), 3.3-2.4 (m, 6H), 2.13 (t, 2H), 1.51-1.39 (m, 2H),1.34-1.18 (m, 2H), 0.89-0.82 (m, 3H); keto tautomer (72%), δ=3.57 (s,2H), 2.88 (s, 3H), 2.80 (s, 3H), 2.50-2.48 (m, 2H), 1.51-1.39 (m, 2H),1.34-1.18 (m, 2H), 0.89-0.82 (m, 3H).

P. 3-oxopentaneamide

0.8 mol (100 ml) methyl-3-oxovalerate (3-oxo-pentanoic acid methylester)and 220 ml 7 N ammonia solution in methanol was stirred for 4 hours at110° C. in a pressure reactor. After cooling off, the solvents weredistilled off on a rotavap, the raw product was taken up in 100 mlethanol and filtrated. The filtrate was concentrated, the residue wasdissolved in 40 ml dimethylether and left to stand at +5° C. for 2 days.The product, which had crystallized in fine needles, was filtrated offand dried in a vacuum drying cabinet at 50° C. 7.10 g of the titlecompound was obtained.

IR (in substance, cm⁻¹): 3370, 3177, 2974, 2937, 2878, 1705, 1651, 1620,1440, 1384, 1355, 1301, 1268, 1189, 1109, 1043, 999, 911, 863, 804, 740,659.

Elemental analysis: C, 51.48; H, 7.924; N, 12.28.

¹H-NMR (DMSO-d₆, 400 MHz): δ [ppm]=enol tautomer (12%), δ=14.5 (s, 1H),7.45 (s, 1H), 7.01 (s, 1H), 4.93 (s, 1H), 2.09 (q, 2H), 1.00 (t, 3H);keto tautomer (88%), δ=7.45 (s, 1H), 7.01 (s, 1H), 3.24 (s, 2H), 2.5 (qsuperposed, 2H), 0.90 (t, 3H).

Q. N,N-dimethyl-3-oxopentaneamide

0.8 mol (100 ml) methyl-3-oxovalerate (3-oxo-pentanoic acid methylester)and 250 ml 33% dimethylamine solution in ethanol (approx. 1.4 moldimethylamine) was stirred for 4 hours at 110° C. in a pressure reactor.After cooling off, the solvents were distilled off on a rotavap, the rawproducts were taken up in 40 ml water, 30 ml 32% HCl and 40 ml ethanoland stirred for 24 hours at 100° C. The mixture was again concentratedto dryness by evaporation, taken up again in 300 ml acetic ester andfiltrated. The filtrate was concentrated to dryness by evaporation andthe product was completely dried under an oil-pump vacuum. 25.8 g of thetitle compound was obtained.

IR (in substance, cm⁻¹): 2976, 2939, 1717, 1637, 1500, 1459, 1396, 1376,1357, 1298, 1262, 1198, 1142, 1107, 1055, 967, 912, 775, 647, 611.

Elemental analysis: C, 54.78; H, 8.724; N, 9.20.

¹H-NMR (DMSO-d₆, 400 MHz): δ [ppm]=enol tautomer (12%), δ=15.1 (s, 1H),5.31 (s, 1H), 2.89 (s, 3H), 2.81 (s, 3H), 2.15 (q, 2H), 1.04 (t, 3H);keto tautomer (87%), δ=3.57 (s, 2H), 2.89 (s, 3H), 2.81 (s, 3H), 2.49(q, 2H), 0.91 (t, 3H).

R. 3-oxo-2-(piperidin-1-ylcarbonyl)butanenitrile

In a nitrogen atmosphere, 45.6 (0.30 mol) 1-cyanoacetylpiperidin wasprovided in 800 ml THF (dry). 18.7 g (0.47 mol) NaH (60% mineral oilsuspension) was added such that the inner temperature did not exceed 10°C. (cooling with an ice/NaCl bath). This was followed by stirring for 30min at 0-10° C. 20 ml (0.28 mol) acetylchloride were dosed in in such away that the inner temperature did not exceed 10° C. The reactionmixture was subsequently stirred for 1 hour at 45° C. Then, 40 ml aceticacid were added slowly, the reaction mixture was put on 2.0 l ice waterand 50 ml HCl (20% m/m) were dosed in. The mixture was shaken out with500 ml toluene, the organic phase was separated, dried over 120 g Na₂SO₄and filtrated. The solution was concentrated at 40° C./80 mbar on therotavap to form an oil and was cooled with a mixture of ice and commonsalt. The precipitated solid was filtrated off, washed with 50 ml coldtoluene, and dried for at least 15 hours at 50° C./<100 mbar. 35.1 g ofproduct was obtained as a solid.

IR (in substance, cm⁻¹): 3009, 2943, 2863, 2206, 2147, 1763, 1659, 1573,1483, 1455, 1275, 1229, 1131, 1022, 969.

Elemental analysis: C, 60.22; H, 9.69; N, 8.75.

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=1.56-1.67 (m, 6H), 2.27 (s, 3H), 3.66(t, 4H), 17.17 (br. s, 1H).

S. N-butyl-3-oxobutaneamide

14.64 g (0.2 mol) n-butylamine and 200 mg DMAP were provided in 60 mlTHP (dry) and 16.8 g (0.2 mol) diketene was dosed in at −5 to 5° C. Thereaction mixture was then stirred for 2 hours at 20-25° C. and thenconcentrated on the rotavap. The residue was dried for at least 15 hoursat 50° C./<100 mbar. 16.0 g of product was obtained.

IR (in substance, cm⁻¹): 3271, 3097, 2959, 2928, 2867, 1714, 1644, 1561,1459, 1421, 1357, 1227, 1163, 1000, 968, 759, 724, 656, 619.

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=0.86-0.94 (m, 3H), 1.26-1.71 (m, 4H),2.23 (s, 3H), 3.23 (q, 2H), 3.36 (s, 2H), 7.00 (br. s, 1H).

T. N,N-dibutyl-3-oxobutaneamide

16.8 g (0.20 mol) diketene was provided in 60 ml THF under nitrogen andthe solution was cooled to approximately −10° C. by means of an ice/NaClmixture. 25.6 g (0.20 mol) di-n-butylamine were then dosed in in such away that the inner temperature did not exceed 0° C. The reaction mixturewas subsequently stirred for 1 hour at −10 to 0° C., and then for 2hours at 20-25° C. The solvent of the reaction mixture was distilled offon the rotavap at 50° C./<100 mbar. 45.9 g of product was obtained as anoil.

10 g each of this raw product was put on 200 g silica gel and elutedwith 2 l acetic ester/n-hexane (2:1 v/v). The eluate was concentrated toform an oil on the rotavap at 50° C. 7<100 mbar and dried further for atleast 15 hours under high vacuum at 20-25° C. 31.5 g of product wasobtained as an oil.

IR (in substance, cm⁻¹): 2958, 2932, 2873, 1722, 1635, 1590, 1490, 1458,1431, 1392, 1372, 1292, 1226, 1144, 1113, 1037, 1007, 931, 774, 732,683.

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]/keto tautomer β=0.87-0.92 (m, 3H),1.25-1.31 (m, 2H), 1.47-1.50 (m, 2H), 2.23 (s, 3H), 3.26-3.30 (m, 2H),3.45 (s, 2H); enol tautomer β=0.87-0.92 (m, 3H), 1.25-1.31 (m, 2H),1.47-1.50 (m, 2H), 1.91 (m, 3H), 3.13-3.17 (m, 2H), 5.00 (s, 1H), 14.95(br. s, 1H).

U. Not Awarded V. N,N-dibutyl-3-oxopentanamide

0.16 mol (20 ml) of methyl 3-oxovalerate (3-oxo-pentanoic acid methylester) and 0.415 mol (70 ml) of dibutylamine were stirred for 3 h at130° C., where methanol formed was removed via a distillation bridge.Thereafter, excess dibutylamine was distilled on a rotary evaporator,the crude product taken up in 40 ml water and 90 ml of ethanol, with 3ml 20% HCl adjusted to pH 3 and stirred for 1 h at 50° C. The mixturewas again evaporated to dryness, dissolved again in 200 ml ethyl acetateand washed 3 times with 100 ml of water. The organic phase was driedover Na₂SO₄ and after filtration evaporated in a rotary evaporator todryness. After drying, 31.8 g of the title compound were obtained.

IR (neat, cm⁻¹): 2959, 2933, 2874, 1721, 1631, 1589, 1490, 1458, 1429,1393, 1374, 1320, 1292, 1250, 1223, 1188, 1144, 1111, 1061, 940, 914,800, 775, 732, 689, 635.

CHN-Elemental analysis: C, 68.22; H, 11.336; N, 6.51.

LC-MS: M+H⁺228.5; M+Na⁺250.5.

1H-NMR (DMSO-d₆, 400 MHz): Enol-Tautomer (40%), δ=15.1 (s, 1H), 5.31 (s,1H), 2.89 (s, 3H), 2.81 (s, 3H), 2.15 (q, 2H), 1.04 (t, 3H);Keto-Tautomer (60%), δ=3.57 (s, 2H), 2.89 (s, 3H), 2.81 (s, 3H), 2.49(q, 2H), 0.91 (t, 3H).

W. 2-Fluoro-N,N-dimethyl-3-oxobutanamide

0.2 mol (25 ml) of ethyl 2-fluoroacetoacetat and 107 ml 33%dimethylamine in ethanol (0.6 mol dimethylamine) were stirred for 3 h at70° C. The reaction mixture was evaporated to dryness and 27 g of crudeproduct chromatographed over 350 g silica gel with ethylacetate/methanol 9/1. 13.4 g of the title compound were obtained.

IR (neat, cm⁻¹): 2942, 1729, 1650, 1501, 1403, 1358, 1260, 1217, 1176,1151, 1072, 962, 829, 705, 681, 632, 611.

CHN-Elemental analysis: C, 47.99; H, 6.70; N, 9.05.

LC-MS: M+H⁺148.2; M+Na⁺170.2.

1H-NMR (DMSO-d₆, 400 MHz): δ=5.96 (d (J=48 Hz), 1H), 3.03 (d (J=1.4 Hz),3H), 2.86 (d (J=1.3 Hz), 3H), 2.18 (d (J=4.0 Hz), 3H).

X. 2-Fluoro-3-oxo-N-propylbutanamide

0.8 mol (65.8 ml) of n-propylamine were added dropwise within 0.5 h to0.2 mol (25 ml) of ethyl 2-fluoroacetoacetat. The reaction mixture washeated and then held for 2 h at 60° C. Then it was evaporated todryness, dissolved in 50 ml water and 60 ml ethanol and adjusted with32% HCl to pH 3. It was again evaporated, dissolved in 300 ml ethylacetate, filtered and again evaporated to dryness. 17 g of crude productwas chromatographed over 800 g silica gel with ethyl acetate/hexane 1/1.After drying, 14 g of the title compound were obtained.

IR (neat, cm⁻¹): 3325, 2967, 2938, 2878, 1736, 1665, 1535, 1460, 1441,1421, 1359, 1277, 1235, 1210, 1179, 1150, 1089, 963, 892, 818, 617.

CHN-Elemental analysis: C, 50.61; H, 7.19; N, 8.58.

LC-MS: M+H⁺, 162.7; M+Na⁺184.6.

1H-NMR (DMSO-d₆, 400 MHz): δ=8.47 (s (broad), 1H), 5.49 (d (J=49 Hz),1H), 3.05 (m, 2H), 2.22 (d (J=3.1 Hz), 3H), 2.18 (d (J=4.0 Hz), 3H);1.42 (sextet, 2H); 0.81 (t, 3H).

Y 4-Methoxy-N,N-dimethyl-3-oxobutaneamide

0.17 mol (25 g) of methyl 4-methoxy-acetoacetate and 91 ml 33%dimethylamine in ethanol (about 0.51 mol dimethylamine) were stirred ina pressure reactor for 4 h at 110° C. The reaction mixture was thenevaporated to dryness and 27 g of crude product chromatographed over 350g silica gel with ethyl acetate/methanol 9/1. After drying, 12.4 g ofthe title compound were obtained.

LC-MS: M+H⁺, 160.7; M+Na⁺, 182.6.

1H-NMR (DMSO-d₆, 400 MHz): Enol-Tautomer (21%), δ=15.1 (s, 1H), 5.48 (s,1H), 3.90 (s, 2H), 3.30 (s, 3H), 3.0-2.8 (m, 6H); Keto-Tautomer (79%),δ=4.10 (s, 2H), 3.55 (s, 2H), 3.27 (s, 3H), 2.90 (s, 3H), 2.81 (s, 3H).

Z. N,N,4-Trimethyl-3-oxopentanamide

0.69 mol (100 g) of 4-methyl-3-oxovaleric acid methyl ester and 309 ml33% dimethylamine in ethanol (about 1.73 mol dimethylamine) were stirredin a pressure reactor for 2 hours at 110° C. After cooling, the solventswere distilled on a rotary evaporator. After drying, 93 g of the titlecompound were obtained.

IR (neat, cm⁻¹): 2969, 2934, 2875, 1714, 1630, 1597, 1502, 1467, 1396,1384, 1359, 1322, 1263, 1207, 1162, 1142, 1073, 1047, 972, 927, 892,782, 725, 701, 650, 614.

CHN-Elemental analysis: C, 59.51; H, 9.60; N, 8.47.

LC-MS: M+H⁺, 158.5; M+Na⁺, 180.2.

1H-NMR (DMSO-d₆, 400 MHz): Enol-Tautomer (19%), δ=15.18 (s, 1H), 5.28(s, 1H), 2.87 (s, 3H), 2.80 (s, 3H), 2.35 (heptet, 1H), 1.05 (d, 6H);Keto-Tautomer (81%), δ=3.62 (s, 2H), 2.87 (s, 3H), 2.80 (s, 3H), 2.68(heptet, 1H), 1.00 (d, 6H).

AA. 4-Methyl-1-(morpholin-4-yl)-pentane-1,3-dione

0.351 mol (49.6 ml) of 4-methyl-3-oxovaleric acid methyl ester and 0.369mol (32.3 ml) morpholine were stirred for 14 hours at 110° C. in aDean-Stark apparatus. 8 ml methanol were collected. Subsequently, theexcess starting materials was distilled off for 3 h on a rotaryevaporator (80° C. water bath, 2 mbar). The crude product was dissolvedin 500 ml toluene and extracted with 50 ml of 1 M NaOH and 3 times with50 ml water, and the organic phase was concentrated on a rotaryevaporator to dryness. After drying, 62.2 g of the title compound wereobtained.

IR (neat, cm⁻¹): 2969, 2929, 2858, 1713, 1636, 1587, 1460, 1436, 1385,1361, 1301, 1272, 1243, 1190, 1166, 1113, 1069, 1050, 1036, 984, 964,929, 886, 850, 779, 733, 700, 660, 619.

CHN-Elemental analysis: C, 58.04; H, 8.24; N, 6.95.

LC-MS: M+H⁺, 200 9; M+Na⁺, 222.8.

1H-NMR (DMSO-d₆, 400 MHz): Enol-Tautomer (16%), δ=14.7 (s, 1H), 5.37 (s,1H), 3.57-3.28 (m, 8H), 2.36 (heptet, 1H), 1.06 (d, 6H); Keto-Tautomer(84%), δ=3.70 (s, 2H), 3.57-3.28 (m, 8H), 2.67 (heptet, 1H), 1.00 (d,6H).

AB. 4-Methoxy-1-(morpholin-4-yl)butane-1,3-dione

0.346 mol (50.5 g) of methyl 4-methoxy-acetoacetate and 0.363 mol (31.6g) of morpholine was stirred for 20 h at 110° C. in a Dean-Starkapparatus. There were further added 0.069 mol (6.02 g) of morpholine andstirred further 3 hours. Subsequently, the excess starting materialswere distilled off on a rotary evaporator. 67.3 g of crude product waschromatographed over 600 g silica gel with ethyl acetate/ethanol 9/1.There were 36.9 g of the title compound.

IR (neat, cm⁻¹): 2921, 2857, 2361, 1729, 1633, 1590, 1438, 1362, 1303,1272, 1244, 1199, 1111, 1069, 1038, 1019, 984, 965, 939, 920, 849, 778,718, 681, 631.

LC-MS: M+H⁺, 202.7; M+Na⁺, 224.6.

1H-NMR (DMSO-d₆, 400 MHz): δEnol-Tautomer (14%), δ=14.8 (s, 1H), 5.55(s, 1H), 3.91 (s, 2H), 3.60-3.32 (m, 8H), 3.30 (s, 3H); Keto-Tautomer(86%), δ=4.11 (s, 2H), 3.60 (s, 2H), 3.60-3.32 (m, 8H), 3.28 (s, 3H).

AC. 3-Acetyl-1-methylpyrrolidin-2-one

20.40 g (0.20 mol) of diisopropylamine were placed in 200 ml dry THFunder nitrogen and 80 ml n-butyl lithium in hexane (2.5 M) were addeddropwise. It was allowed to stir for 20 minutes and then 20.00 g (0.20mol) of 1-methyl-2-pyrrolidinone were added dropwise at −78° C. Afterstirring the reaction mixture for 1 hour 17.64 g (0.20 mol) of dry ethylacetate were added at −78° C. The reaction mixture was warmed to roomtemperature and stirred for 14 hours. The THF was removed on a rotaryevaporator under reduced pressure and the residue was taken up in 80 mlof 6 N HCl. The acidic aqueous phase was saturated with NaCl andextracted 5 times with 300 ml ethyl acetate. The combined organic layerswere dried over Na₂SO₄, and the solvent was removed on a rotaryevaporator. The remaining yellow oil was purified by columnchromatography. This gave 5.10 g product as a light yellow oil.

IR (neat, cm⁻¹): 3495, 2929, 2885m 1714, 1674, 1500, 1433, 1403, 1358,1297, 1262, 1166, 1107, 989, 763, 712.

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=1.95 (1H), 2.30 (3H), 2.45 (1H), 2.75(3H), 3.25 (1H), 3.35 (1H), 3.5 (1H).

AD. Ethyl (1-methyl-2-oxopyrrolidin-3-yl)(oxo)acetate

13.20 g of 60% NaH (in paraffin oil) (0.33 mol) was added to 100 ml ofdry diethyl ether. With vigorous stirring, 19.83 g (0.20 mol) ofN-methylpyrrolidone were added. Then within one hour 121.30 g (0.83 mol)of diethyl oxalate were added dropwise. After the addition thesuspension was heated to 40° C. and stirred for 21 hours. The reactionmixture was then cooled in an ice bath, mixed with 66 ml 5M HCl and theresulting 2-phase mixture was filtered once. Then the two phases wereseparated, and the aqueous phase was extracted twice with 100 ml diethylether. The combined ethereal phases were dried over Na₂SO₄ andconcentrated on a rotary evaporator to dryness. The oily residue wascooled to −80° C. and mixed with 200 ml diethyl ether. The resultingbrown solid was filtered off and recrystallized from heptane. This gave5.2 g product as white needles.

IR (neat, cm⁻¹): 3342, 2977, 2939, 1723, 1658, 1581, 1498, 1469, 1448,1373, 1344, 1307, 1269, 1196, 1160, 1117, 1094, 1024, 977, 903, 876,819, 783, 737, 701, 675.

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=1.26 (3H), 2.83 (3H), 2.94 (2H), 3.37(2H), 4.21 (2H), 11.80 (1H).

AE. Ethyl (1-methyl-2-oxopiperidin-3-yl)(oxo)acetate

20.4 g of diisopropylamine (0.1 mol) were dissolved in 200 ml of dry THFunder nitrogen and cooled in a freezing mixture. 80 ml n-butyllithium inhexane (2.5 M, 0.2 mol) were added dropwise slowly. After the additionit was allowed to stir for 60 minutes and then 22.6 gN-methyl-2-piperidone (0.2 mol) were added dropwise. The reactionmixture was stirred for another 20 min in the freezing mixture. In asecond flask, 87.7 g diethyl oxalate (0.6 mol) in 100 ml of dry THF werecooled in a freezing mixture and the cooled reaction mixture wascannulated with stirring in small portions to it. It was left overnightunder stirring to warm to room temperature. The THF was removed on arotary evaporator and the residue was taken up in 80 ml halfconcentrated hydrochloric acid. The aqueous phase was extracted fivetimes with 300 ml ethyl acetate, the combined organic phases were driedover sodium sulfate and concentrated on a rotary evaporator to dryness.The excess diethyl oxalate was removed by distillation (2-3 mbar, 80°C.) and 45 g of crude product were obtained. 10.4 g product was obtainedas white crystals with a melting point of 23° C. after crystallizationfrom diethyl ether/n-hexane.

IR (neat, cm⁻¹): 2981, 2935, 1721, 1610, 1503, 1449, 1393, 1371, 1331,1304, 1247, 1223, 1193, 1095, 1081, 1028, 995, 944, 895, 860, 794, 758,722, 671, 628.

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=14.00 (1H), 4.20 (2H), 3.25 (2H), 2.90(3H), 2.65 (2H), 1.73 (2H), 1.23 (3H).

AF. 3-Acetyl-1-methyl-piperidin-2-one

20.6 g of diisopropylamine (0.2 mol) were placed in 200 ml of dry THFunder nitrogen and cooled to −80° C. 80 ml n-butyllithium in hexane (2.5M, 0.2 mol) were slowly added dropwise. After the addition it wasallowed to stir for 15 min and then 22.6 g N-methyl-2-piperidone (0.2mol) were added dropwise. The reaction mixture was stirred for 30 minand then 17.6 g of dry ethyl acetate (0.2 mol) was added. The reactionmixture with stirring overnight was allowed to warm to room temperature.The THF was removed on a rotary evaporator and the residue was taken upin 80 ml 6M HCl. The aqueous phase was extracted five times with 100 mlethyl acetate. The combined organic layers were dried over sodiumsulfate and the solvent was removed on a rotary evaporator. The product(keto form:enol form=1:1) was fractionated by distillation at 0.6 mbarand obtained as a yellowish liquid (bp 70° C.).

IR (neat, cm⁻¹): 3506, 2940, 2865, 1715, 1632, 1597, 1498, 1463, 1443,1401, 1386, 1354, 1330, 1310, 1252, 1203, 1160, 1118, 1081, 983, 952,887, 762, 686, 651, 606.

Enol form:

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=1.81 (2H), 1.92 (3H), 2.38 (2H), 2.96(3H), 3.30 (2H), 14.8 (1H).

Keto form:

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=1.81 (3H), 2.14 (1H), 2.34 (3H), 2.99(3H), 3.30 (2H), 3.48 (1H).

AG. Ethyl 4-(dimethylamino)-2,4-dioxobutanoate

10.2 g of diisopropylamine (0.1 mol) were dissolved in 100 ml of dry THFunder nitrogen and cooled in a freezing mixture. 40 ml n-butyllithium inhexane (2.5 M, 0.1 mol) were slowly added dropwise. When the additionwas completed it was allowed to stir for 60 minutes and then 8.7 gN,N-dimethylacetamide (0.1 mol) were added dropwise. The reactionmixture was stirred for another 20 min in the freezing mixture. In asecond flask, 43.7 g of diethyl oxalate (0.3 mol) in 50 ml of dry THFwere cooled in a freezing mixture and the cooled reaction mixture wascannulated with stirring in small portions to it. It was left overnightunder stirring to warm to room temperature. The THF was removed on arotary evaporator and the residue was taken up in 80 ml halfconcentrated hydrochloric acid. The aqueous phase was extracted fivetimes with 150 ml ethyl acetate, the combined organic phases dried oversodium sulfate and concentrated on a rotary evaporator to dryness. Theexcess diethyl oxalate was removed by distillation (2-3 mbar, 80° C.)and 17 g of crude product were obtained. 5.5 g product was obtained aswhite crystals with a melting point of 28° C. after crystallization fromn-hexane.

IR (neat, cm⁻¹): 2984, 2941, 1738, 1620, 1507, 1467, 1393, 1370, 1355,1313, 1260, 1170, 1126, 1016, 927, 860, 823, 772, 723, 628.

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=1.38 (3H), 3.06 (6H), 4.33 (2H), 6.25(1H)

AH. 1-(Morpholin-4-yl)butane-1,3-dione

33 ml (0.38 mol) of morpholine were added dropwise at −5 to 0° C. to asolution of 30 g of diketene (0.36 mol) in 300 ml tetrahydrofuran. After1 h stirring at 0° C. no more starting material was detected by thinlayer chromatography. The reaction mixture was evaporated and theresidue purified by column chromatography. This gave 49.48 g (0.29 mol,81% yield) of a white solid.

IR (neat, cm⁻¹): 2965, 2918, 2858, 1718, 1633, 1587, 1488, 1436, 1359,1303, 1273, 1245, 1220, 1112.

CHN-Elemental analysis: C, 56.03; H, 7.62; N, 8.12.

LC-MS: 172 (M+H), 194 (M+Na).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=3.6 bis 3.3 (10H), 2.2 (3H).

AI. N-(2-Methoxyethyl)-3-oxobutanamide

33 ml (0.38 mol) methoxyethylamine were added dropwise to a solution of30 g of diketene (0.36 mol) in 300 ml tetrahydrofuran at −5 to 0° C.After 1 h stirring at 0° C. no more starting material was detected bythin layer chromatography. The reaction mixture was evaporated and theresidue purified by column chromatography. This gave 47.15 g (0.30 mol,83% yield) of a white solid.

IR (neat, cm⁻¹): 3291, 3095, 2978, 2922, 2887, 2851, 1709, 1643, 1560,1417, 1356, 1344, 1297, 1195, 1166, 1122, 1092.

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=7.1 (1H), 3.4 bis 3.3 (9H), 2.2 (3H).

AJ. N-Cyclopropyl-3-oxobutanamide

26 ml (0.38 mmol) cyclopropylamine was added dropwise to a solution of30 g of diketene (0.36 mol) in 300 ml tetrahydrofuran at −5 to 0° C.After 1 h stirring at 0° C. no more starting material was detected bythin layer chromatography. The reaction mixture was evaporated and theresidue purified by column chromatography. This gave 43.83 g (0.31 mol,87% yield) of a white solid.

IR (neat, cm⁻¹): 3266, 3082, 3017, 2953, 2922, 1724, 1666, 1636, 1450,1421, 1358, 1338, 1221, 1193, 1161, 1014.

LC-MS: 140 (M−H).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=7.2 (1H), 3.4 (2H), 2.7 (1H), 2.2 (3H),0.7 (2H), 0.5 (2H).

AK. 3-Oxo-N-(propan-2-yl)butanamide

32 ml (0.38 mmol) of isopropylamine were added dropwise to a solution of30 g of diketene (0.36 mol) in 300 ml tetrahydrofuran at −5 to 0° C.After 1 h stirring at 0° C. no more starting material was detected bythin layer chromatography. The reaction mixture was evaporated and theresidue purified by column chromatography. This gave 40.36 g (0.28 mol,79% yield) of a white solid.

IR (neat, cm⁻¹): 3254, 3088, 2975, 2925, 1725, 1633, 1561, 1459, 1422,1350, 1334, 1314, 1289, 1190, 1160, 1133.

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=6.9 (1H), 4.0 (1H), 3.3 (2H), 2.2 (3H),1.1 (6H).

AL. N-(2-Hydroxyethyl)-3-oxobutanamide

23 ml (0.38 mmol) of ethanolamine were added dropwise to a solution of30 g of diketene (0.36 mol) in 300 ml tetrahydrofuran at −5 to 0° C.After 1 h stirring at 0° C. no more starting material was detected bythin layer chromatography. The reaction mixture was evaporated and theresidue purified by column chromatography. This gave 41.44 g (0.29 mol,80% yield) as a white solid.

IR (neat, cm⁻¹): 3273, 3097, 2973, 2938, 2880, 1710, 1646, 1558, 1494,1465, 1420, 1362, 1347, 1312, 1297, 1215, 1190, 1166, 1052, 1038.

CHN-Elemental analysis: C, 49.13; H, 7.76; N, 9.71.

LC-MS: 145 (M), 127 (M−H2O).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=7.5 (1H), 3.7 (2H), 3.4 (4H), 2.2 (3H).

AM. N-(3-hydroxypropyl)-3-oxobutanamide

28 ml (0.38 mmol) of 3-amino-1-propanol were added dropwise to asolution of 30 g of diketene (0.36 mol) in 300 ml tetrahydrofuran at −5to 0° C. After 1 h stirring at 0° C. no more starting material wasdetected by thin layer chromatography. The reaction mixture wasevaporated and the residue purified by column chromatography. This gave47.15 g (0.30 mol, 83% yield) of a white solid.

IR (neat, cm⁻¹): 3295, 3090, 2940, 2877, 1715, 1643, 1545, 1470, 1416,1358, 1324, 1213, 1160, 1056, 963.

LC-MS: 182 (M+Na), 160 (M+H), 142 (M−OH).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=7.4 (1H), 3.6 (3H), 3.3 (4H), 2.2 (3H),1.6 (2H).

AN. N-(4-Hydroxybutyl)-3-oxobutanamide

A solution of 22 ml (0.24 mol) of 4-amino-1-butanol in 50 mltetrahydrofuran was added dropwise to a solution of 20 g of diketene(0.24 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirringat 0° C. no more starting material was detected by thin layerchromatography. The reaction mixture was evaporated and the residuepurified by column chromatography. This gave 35.43 g (0.21 mol, 86%yield) of a white solid.

IR (neat, cm⁻¹): 3273, 3098, 2933, 2866, 1712, 1644, 1555, 1418, 1361,1344, 1322, 1188, 1167, 1060.

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=7.4 (1H), 3.6 (2H), 3.3 (2H), 3.2 (2H),3.1 (1H), 2.22 (3H), 1.5 (4H).

AO-1. N-(5-Hydroxypentyl)-3-oxobutanamide

A solution of 39 g (0.38 mol) of 5-amino-1-pentanol in 300 mltetrahydrofuran was added dropwise to a solution of 30 g of diketene(0.36 mol) in 300 ml tetrahydrofuran at −5 to 0° C. After 1 h stirringat 0° C. no more starting material was detected by thin layerchromatography. The reaction mixture was evaporated and the residuepurified by column chromatography. This gave 52.70 g (0.28 mol, 79%yield) as a white solid.

IR (neat, cm⁻¹): 3269, 3096, 2928, 2855, 1725, 1711, 1643, 1418, 1361,1340, 1190, 1166, 1060, 1007.

LCMS: 188 (M+H).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=7.2 (1H), 3.6 (2H), 3.4 (2H), 3.2 (2H),2.8 (1H), 2.2 (3H), 1.5 (4H), 1.3 (2H).

AO-2. N-(1-Hydroxy-2-methylpropan-2-yl)-3-oxobutanamide

A solution of 33.40 g (0.38 mol) 2-amino-2-methyl-1-propanol in 300 mlof tetrahydrofuran was added dropwise to a solution of 30 g of diketene(0.36 mol) in 300 ml of tetrahydrofuran at −5 to 0° C. After 1 hstirring at 0° C. no more starting material was detected by thin layerchromatography. The reaction mixture was evaporated and the residuepurified by column chromatography. This gave 50.00 g (0.29 mol, 81%yield) of a white solid.

IR (neat, cm⁻¹): 3308, 2973, 2932, 1714, 1646, 1545, 1456, 1412, 1359,1331, 1267, 1160, 1057.

CHN-Elemental analysis: C, 54.99; H, 8.67; N, 8.42.

LCMS: 172 (M−H).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=7.1 (1H), 4.6 (1H), 3.5 (2H), 3.3 (2H),2.2 (3H), 1.3 (3H).

AP. N-(2-Hydroxyethyl)-N-methyl-3-oxobutanamide

A solution of 30 ml (0.38 mol) 2-(methylamino)ethanol in 300 mltetrahydrofuran was added dropwise to a solution of 30 g of diketene(0.36 mol) in 300 ml tetrahydrofuran at −5 to 0° C. After 1 h stirringat 0° C. no more starting material was detected by thin layerchromatography. The reaction mixture was evaporated and the residuepurified by column chromatography. This gave 41.46 g (0.26 mol, 73%yield) of a white solid.

IR (neat, cm⁻¹): 3407, 2934, 1717, 1620, 1491, 1401, 1357, 1308, 1161,1121, 1050, 928, 861, 778.

LCMS: 159 (M), 141 (M−H2O).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=3.7 (3H), 3.5 (2H), 3.3 (1H), 3.0 (2H),2.9 (1H), 2.2 (3H).

AQ. N-(2-Hydroxypropyl)-3-oxobutanamide

19 ml (0.24 mol) 1-amino-2-propanol were added dropwise to a solution of20 g of diketene (0.24 mol) in 200 ml tetrahydrofuran at −5 to 0° C.After 1 h stirring at 0° C. no more starting material was detected bythin layer chromatography. The reaction mixture was evaporated and theresidue purified by column chromatography. This gave 29.50 g (0.19 mol,78% yield) of a colorless oil.

IR (neat, cm⁻¹): 3307, 3088, 2972, 2930, 1714, 1643, 1545, 1415, 1359,1326, 1161, 1134, 1090.

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=7.4 (1H), 3.9 (1H), 3.8 (1H), 3.3 (2H),3.1 (2H), 2.2 (3H), 1.1 (3H).

AR. N-(1-Hydroxypropan-2-yl)-3-oxobutanamide

19 ml (0.24 mol) of 2-amino-1-propanol were added dropwise to a solutionof 20 g of diketene (0.24 mol) in 200 ml tetrahydrofuran at −5 to 0° C.After 1 h stirring at 0° C. no more starting material was detected bythin layer chromatography. The reaction mixture was evaporated and theresidue purified by column chromatography. This gave 27.12 g (0.17 mol,71% yield) of a colorless oil.

IR (neat, cm⁻¹): 3295, 3083, 2974, 2935, 2877, 1714, 1640, 1544, 1454,1413, 1358, 1324, 1220, 1160, 1095, 1050, 992.

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=7.2 (1H), 4.0 (1H), 3.9 (1H), 3.6 (1H),3.4 (2H), 2.2 (3H), 1.1 (3H).

AS. N-(1-Hydroxybutan-2-yl)-3-oxobutanamide

34 ml (0.36 mol) of 2-amino-1-butanol were added dropwise to a solutionof 30 g of diketene (0.36 mol) in 300 ml tetrahydrofuran at −5 to 0° C.After 1 h stirring at 0° C. no more starting material was detected bythin layer chromatography. The reaction mixture was evaporated and theresidue purified by column chromatography. This gave 46.97 g (0.27 mol,76% yield) of a colorless oil.

IR (neat, cm⁻¹): 3294, 3085, 2986, 2936, 2878, 1714, 1640, 1544, 1461,1414, 1358, 1218, 1160, 1089, 1052.

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=7.2 (1H), 3.8 (1H), 3.6 (1H), 3.5 (1H),3.4 (1H), 3.3 (1H), 2.2 (3H), 1.5 (1H), 1.4 (1H), 0.8 (3H).

AT. N-(2,3-Dihydroxypropyl)-3-oxobutanamide

A solution of 22.5 g (0.21 mol) 3-methylamino-1,2-propanediol in 200 mlof tetrahydrofuran was added dropwise to a solution of 18 g of diketene(0.21 mol) in 200 ml of tetrahydrofuran at −5 to 0° C. After 1 hstirring at 0° C. no more starting material was detected by thin layerchromatography. The reaction mixture was evaporated and the residuepurified by column chromatography. This gave 32.00 g (0.17 mol, 79%yield) of a colorless oil.

IR (neat, cm⁻¹): 3385, 2931, 1716, 1616, 1492, 1403, 1358, 1310, 1162,1103, 1040, 925.

LC-MS: 212 (M+Na), 190 (M+H), 172 (M−OH).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=3.9 (1H), 4.8 bis 3.3 (8H), 3.1 (3H),2.3 (3H).

AU. 1-(3-Hydroxypiperidin-1-yl)butane-1,3-dione

A solution of 36.10 g (0.36 mol) of 3-hydroxypiperidine in 300 mltetrahydrofuran was added dropwise to a solution of 30 g of diketene(0.36 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirringat 0° C. no more starting material was detected by thin layerchromatography. The reaction mixture was evaporated and the residuepurified by column chromatography. This gave 53.53 g (0.29 mol, 81%yield) of a white solid.

IR (neat, cm⁻¹): 3340, 1716, 1618, 1596, 1485, 1462, 1437, 1410, 1360,1343, 1319, 1279, 1263, 1185, 1159, 1138, 1001, 921, 858.

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=3.8 (2H), 3.6 bis 3.2 (5H), 2.9 (1H),2.2 (3H), 1.8 (2H), 1.6 (1H), 1.4 (1H).

AV. 1-[4-(Hydroxymethyl)piperidin-1-yl]butane-1,3-dione

A solution of 25 g (0.22 mol) of 4-piperidine methanol in 200 mltetrahydrofuran was added dropwise to a solution of 18 g of diketene(0.2 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at0° C. no more starting material was detected by thin layerchromatography. The reaction mixture was evaporated and the residuepurified by column chromatography. This gave 35.40 g (0.18 mol, 83%yield) of a colorless oil.

IR (neat, cm⁻¹): 3401, 3003, 2918, 2860, 1718, 1618, 1447, 1358, 1313,1270, 1200, 1158, 1089, 1036, 987, 956.

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=4.5 (1H), 3.7 (1H), 3.4 (2H), 3.3 (2H),2.9 (1H), 2.6 (1H), 2.5 (1H), 2.2 (3H), 1.7 (3H), 1.1 (2H).

AW. 1-[3-(Hydroxymethyl)piperidin-1-yl]butane-1,3-dione

A solution of 25 g (0.22 mol) of 3-piperidinemethanol in 200 mltetrahydrofuran was added dropwise to a solution of 18 g of diketene(0.2 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at0° C. no more starting material was detected by thin layerchromatography. The reaction mixture was evaporated and the residuepurified by column chromatography. This gave 31.50 g (0.16 mol, 74%yield) of a colorless oil.

IR (neat, cm⁻¹): 3411, 2926, 2859, 1717, 1618, 1442, 1358, 1308, 1262,1222, 1183, 1160, 1036, 855.

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=4.1 (1H), 3.6 bis 3.2 (7H), 2.9 (1H),2.2 (3H), 1.7 (3H), 1.3 (2H).

AX. 1-[2-(Hydroxymethyl)piperidin-1-yl]butane-1,3-dione

A solution of 25 g (0.22 mol) 2-piperidinemethanol in 200 mltetrahydrofuran was added dropwise to a solution of 18 g of diketene(0.2 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at0° C. no more starting material was detected by thin layerchromatography. The reaction mixture was evaporated and the residuepurified by column chromatography. This gave 32.40 g (0.17 mol, 76%yield) of a colorless oil.

IR (neat, cm⁻¹): 3403, 2936, 1717, 1612, 1442, 1357, 1309, 1267, 1226,1158, 1139, 1049.

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=4.7 (1H), 4.4 (1H), 3.9 bis 3.7 (2H),3.6 bis 3.3 (3H), 2.2 (3H), 1.7 bis 1.3 (6H).

AY. 1-[(3S)-3-Hydroxypyrrolidin-1-yl]butane-1,3-dione

A solution of 21.8 g (0.25 mol) (S)-3-pyrrolidinol in 200 mltetrahydrofuran was added dropwise to a solution of 20 g of diketene(0.24 mol) in 200 ml of tetrahydrofuran at −5 to 0° C. added. After 1 hstirring at 0° C. no more starting material was detected by thin layerchromatography. The reaction mixture was evaporated and the residuepurified by column chromatography. This gave 31.35 g (0.18 mol, 77%yield) of a colorless oil.

IR (neat, cm⁻¹): 3390, 2948, 1717, 1616, 1438, 1383, 1357, 1224, 1188,1160, 1102, 988, 871.

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=4.4 (1H), 4.1 (1H), 3.6 bis 3.3 (5H),2.2 (3H), 2.0 bis 1.8 (3H).

AZ. 1-[4-(2-Hydroxyethyl)piperazin-1-yl]butane-1,3-dione

A solution of 32.5 g (0.25 mol) 1-(2-hydroxyethyl)piperazine in 100 mltetrahydrofuran was added dropwise to a solution of 20 g of diketene(0.24 mol) in 200 ml of tetrahydrofuran at −5 to 0° C. After 1 hstirring at 0° C. no more starting material was detected by thin layerchromatography. The reaction mixture was evaporated and the residuepurified by column chromatography. This gave 36.10 g (0.17 mol, 71%yield) of a colorless oil.

IR (neat, cm⁻¹): 3412, 2922, 2812, 1717, 1628, 1441, 1357, 1305, 1156,1051, 1001, 875.

LC-MS: 237 (M+Na), 215 (M+H).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=3.6 (4H), 3.5 (2H), 3.4 (2H), 2.7 (1H),2.6 (2H), 2.5 (4H), 2.2 (3H).

AAA. 1-(4-Methylpiperazin-1-yl)butane-1,3-dione

28 ml (0.25 mol) 1-(2-hydroxyethyl)piperazine was added dropwise to asolution of 20 g of diketene (0.24 mol) in 300 ml tetrahydrofuran at −5to 0° C. After 1 h stirring at 0° C. no more starting material wasdetected by thin layer chromatography. The reaction mixture wasevaporated and the residue purified by column chromatography. This gave33.70 g (0.18 mol, 77% yield) of a colorless oil.

IR (neat, cm⁻¹): 2938, 2847, 2792, 1719, 1633, 1586, 1488, 1440, 1338,1358, 1291, 1257, 1141, 1050, 1001, 778.

LC-MS: 207 (M+Na), 185 (M+H).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=3.6 (2H), 3.5 (2H), 3.4 (2H), 2.4 (4H),2.3 (3H), 2.2 (3H).

AAB. N-(3-Hydroxypropyl)-N-methyl-3-oxobutanamide

A solution of 20 g (0.23 mol) of 3-methylamino-1-propanol in 50 mltetrahydrofuran was added dropwise to a solution of 18 g of diketene(0.21 mol) in 200 ml tetrahydrofuran −5 to 0° C. After 1 h stirring at0° C. no more starting material was detected by thin layerchromatography. The reaction mixture was evaporated and the residuepurified by column chromatography. This gave 29.2 g (0.17 mol, 79%yield) of a colorless oil.

IR (neat, cm⁻¹): 3407, 2936, 1718, 1622, 1493, 1402, 1358, 1310, 1161,1128, 1058, 945.

LC-MS: 156 (M−OH), 174 (M+H), 196 (M+Na).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=3.8 bis 3.4 (7H), 2.9 (3H), 2.2 (3H),1.7 (2H).

AAC. N-(trans-4-Hydroxycyclohexyl)-3-oxobutanamide

A solution of 28.8 g (0.25 mol) trans-4-aminocyclohexanol in 200 mltetrahydrofuran was added dropwise to a solution of 20 g of diketene(0.24 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirringat 0° C. no more starting material was detected by thin layerchromatography. The reaction mixture was evaporated and the residue isrecrystallized from 200 ml of ethyl acetate. This gave 33.6 g (0.17 mol,71% yield) of a colorless solid.

IR (neat, cm⁻¹): 3274, 2940, 2859, 1716, 1639, 1543, 1450, 1423, 1338,1221, 1136, 1098, 1058, 1009, 963, 948, 900.

LC-MS: 200 (M+H), 222 (M+Na).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=6.9 (1H), 3.7 (1H), 3.6 (1H), 3.3 (2H),2.5 (1H), 2.2 (3H), 1.9 (4H), 1.4 bis 1.1 (4H).

AAD. N-(3-Hydroxy-2,2-dimethylpropyl)-3-oxobutanamide

A solution of 32.2 g (0.31 mol) of 3-amino-2,2-dimethyl-propan-1-ol in60 ml tetrahydrofuran was added dropwise to a solution of 25 g ofdiketene (0.30 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 hstirring at 0° C. no more starting material was detected by thin layerchromatography. The reaction mixture was evaporated and the residue isrecrystallized from 150 ml of ethyl acetate. This gave 40.6 g (0.21 mol,73% yield) of a colorless solid.

IR (neat, cm⁻¹): 3253, 3099, 2957, 2873, 1724, 1637, 1581, 1476, 1453,1428, 1358, 1325, 1162, 1035, 995, 785.

LC-MS: (M+H), (M+Na).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=7.5 (1H), 3.8 (1H), 3.4 (2H), 3.1 (4H),2.3 (3H), 0.8 (6H).

AAE. 1-[4-(Dimethylamino)piperidin-1-yl]butane-1,3-dione

20 g (0.16 mol) of 4-piperidine-dimethylamine were added dropwise to asolution of 12.5 g of diketene (0.15 mol) in 200 ml tetrahydrofuran at−5 to 0° C. After 1 h stirring at 0° C. no more starting material wasdetected by thin layer chromatography. The reaction mixture wasevaporated and the residue purified by column chromatography. This gave23.9 g (0.11 mol, 76% yield) of a colorless oil.

IR (neat, cm⁻¹): 3270, 2930, 2863, 2721, 1719, 1633, 1585, 1492, 1448,1389, 1360, 1270, 1238, 1198, 1154, 1060, 1040, 958, 873, 775.

LC-MS: 213 (M+H), 235 (M+Na).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=4.5 (1H), 3.7 (1H), 3.5 (2H), 3.0 (1H),2.6 (1H), 2.3 (1H), 2.2 (9H), 1.8 (2H), 1.3 (2H).

AAF. 1-(4-Methoxypiperidin-1-yl)butane-1,3-dione

15 g (0.13 mol) of 4-methoxy-piperidine were added dropwise to asolution of 10.4 g of diketene (0.12 mol) in 200 ml tetrahydrofuran at−5 to 0° C. After 1 h stirring at 0° C. no more starting material wasdetected by thin layer chromatography. The reaction mixture wasevaporated and the residue purified by column chromatography. This gave17.0 g (0.085 mol, 71% yield) of a colorless oil.

IR (neat, cm⁻¹): 2930, 2863, 1720, 1635, 1586, 1488, 1445, 1390, 1359,1270, 1188, 1097, 1077, 1067, 1024, 939, 904.

LC-MS: 200 (M+H), 223 (M+Na).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=3.8 bis 3.2 (8H), 2.2 (3H), 1.8 (4H),1.5 (2H).

AAG. 1-(2,6-Dimethylmorpholin-4-yl)butane-1,3-dione

23 ml (0.19 mol) of 2,6-dimethylmorpholine were added dropwise to asolution of 15 g of diketene (0.18 mol) in 200 ml tetrahydrofuran at −5to 0° C. After 1 h stirring at 0° C. no more starting material wasdetected by thin layer chromatography. The reaction mixture wasevaporated and the residue purified by column chromatography. This gave26.5 g (0.13 mol, 74% yield) of a colorless oil.

IR (neat, cm⁻¹): 3683, 2974, 2863, 1720, 1635, 1440, 1377, 1359, 1322,1246, 1223, 1171, 1139, 1083, 1035, 966, 839.

LC-MS: 200 (M+H), 223 (M+Na).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=4.4 (1H), 4.0 (1H), 3.6 bis 3.3 (3H),2.8 (1H), 2.4 (1H), 2.3 (1H), 2.2 (3H), 1.1 (6H).

AAH. N-(Morpholin-4-yl)-3-oxobutanamide

18 ml (0.19 mol) of 4-Aminomorpholine were added dropwise to a solutionof 15 g of diketene (0.18 mol) in 200 ml tetrahydrofuran at −5 to 0° C.After 1 h stirring at 0° C. no more starting material was detected bythin layer chromatography. The reaction mixture was evaporated and theresidue purified by column chromatography. This gave 26.1 g (0.14 mol,78% yield) of a colorless oil.

IR (neat, cm⁻¹): 3095, 2940, 2841, 1711, 1677, 1625, 1591, 1504, 1448,1380, 1358, 1302, 1263, 1193, 1163, 1109, 1073, 1038, 912, 869.

LC-MS: 187 (M+H), 210 (M+Na).

¹H-NMR (DMSO, 400 MHz): δ [ppm]=3.8 bis 3.3 (6H), 2.8 bis 2.5 (4H), 2.2(3H), 2.1 (1H).

AAI. 1-(Morpholin-4-yl)pentane-1,3-dione

50.0 g (384 mmol) of 3-oxovaleric acid methyl ester and 35.1 g (403mmol) of morpholine were heated for 9 h at 110° C., whereby the methanolformed was removed via a distillation bridge. The reaction mixture wasthen freed of volatile constituents on a rotary evaporator and purifiedby column chromatography (silica gel, eluent: gradient of ethyl acetateto ethanol). The pure product fractions were freed from solvent on arotary evaporator and yielded 39.7 g (60%) of a viscous, colorless,clear oil.

IR (neat, cm⁻¹): 2973, 2858, 1716, 1633, 1437, 1359, 1301, 1272, 1247,1171, 1111, 1068, 1032, 961, 850, 584.

Elemental analysis: C, 57.26; H, 8.00; N, 7.96.

LC-MS: 186.7 (M+H⁺), 208.7 (M+Na⁺).

¹H-NMR (CDCl₃, 400 MHz): 3.59-3.46 (8H), 3.33 (2H), 2.48 (2H), 0.98(3H).

AAJ. 1-(4-Hydroxypiperidin-1-yl)pentane-1,3-dione

59.0 g (583 mmol) of 4-hydroxypiperidine and 79.7 g (612 mmol) of3-oxovaleric acid methyl ester were heated for 9 h at 110° C., and theresulting methanol was removed via a distillation bridge. The reactionresidue was freed from volatiles on a rotary evaporator, taken up inethanol, and filtered through 600 ml of strongly acidic ion exchanger(Dowex® HCR-W2), concentrated again and purified by columnchromatography (silica gel, eluent's gradient from ethyl acetate toethanol). The pure product fractions were freed from solvent on a rotaryevaporator and yielded 63.6 g (55%) of a viscous, clear, colorless oil.

IR (neat, cm⁻¹): 2940, 2877, 1715, 1616, 1449, 1369, 1299, 1171, 1108,1077, 1059, 1018, 978, 930, 583.

LC-MS: 186.8 (M+H⁺); 208.7 (M+Na⁺).

¹H-NMR (CDCl₃, 400 MHz): 3.85 (2H), 3.60-3.51 (1H), 3.47 (2H), 3.23(1H), 3.18-3.07 (2H), 2.47 (2H), 1.75 (2H), 1.42 (2H), 0.96 (3H).

AAK. N-Butyl-3-oxoheptanamide

0.9 mol (150 ml) of methyl 3-oxoheptanoate and 2.7 mol (270 ml)butylamine, were stirred 5 h at 100° C. in the pressure vessel.Thereafter, excess butylamine was distilled off on a rotary evaporator,the crude product was taken up in water/ethanol, and adjusted withconcentrated HCl to pH 3. The mixture was again evaporated to dryness,taken up again in ethyl acetate and filtered. The filtrate was washedwith 1 M HCl and water. The organic phase was dried over Na₂SO₄ andafter filtration evaporated in a rotary evaporator to dryness. The crudeproduct was dissolved in 100 ml diethyl ether and crystallized at 5° C.The product was filtered off and dried. There were obtained 36.0 g ofthe title compound.

IR (neat, cm⁻¹): 3268, 3098, 2958, 2931, 2873, 1723, 1707, 1641, 1563,1466, 1455, 1434, 1416, 1377, 1350, 1337, 1255, 1227, 1176, 1159, 1125,1098, 1065, 1013, 969, 904, 881, 774, 734, 716, 650.

CHN-Elemental analysis: C, 66.77; H, 10.62; N, 6.93.

LC-MS: M+H⁺, 200.6; M+Na⁺, 222.7.

¹H-NMR (DMSO-d₆, 400 MHz): Enol-Tautomer (12%), δ [ppm]=14.16 (s, 1H),7.82 (m, 1H), 4.92 (s, 1H), 3.1-3.0 (m, 2H), 2.06 (t, 2H), 1.5-1.3 (m,4H), 1.3-1.2 (m, 4H), 0.88-0.82 (m, 6H); Keto-Tautomer (88%), δ=7.97 (m,1H), 3.24 (s, 2H), 3.02 (q, 2H), 2.47 (t, 2H), 1.5-1.3 (m, 4H), 1.3-1.2(m, 4H), 0.88-0.81 (m, 6H).

AAL. 1-(4-Hydroxypiperidin-1-yl)-4-methylpentane-1,3-dione

0.351 mol (49.6 ml) of 4-methyl-3-oxovaleric acid methyl ester and 0.369mol (37.3 g) of 4-hydroxypiperidine were stirred for 6 h at 120° C. in aDean-Stark apparatus. 12 ml of methanol were collected. Subsequently,the excess starting materials were distilled off for 3 h on a rotaryevaporator (80° C. water bath, 2 mbar). 71 g of the title compound wereobtained.

IR (neat, cm⁻¹): 2934, 2873, 1712, 1619, 1449, 1384, 1364, 1330, 1300,1267, 1225, 1187, 1166, 1117, 1071, 1025, 979, 955, 930, 846, 808, 777,733, 693.

CHN-Elemental analysis: C, 50.13; H, 7.514; N, 5.89.

LC-MS: M+H⁺, 214.9; M+Na⁺, 239.9.

¹H-NMR (DMSO-d₆, 400 MHz): Enol-Tautomer (15%), δ [ppm]=5.39 (s, 1H),4.49 (s (broad), 1H), 3.9-2.9 (m, 5H), 2.6-2.5 (m, 1H), 1.75-1.11 (m,4H), 1.06 (d, 6H); Keto-Tautomer (85%), δ=4.73 (s (broad), 1H), 3.67 (s,2H), 3.9-2.9 (m, 5H), 2.68 (heptet, 1H), 1.75-1.11 (m, 4H), 1.00 (d,6H).

AAM. N-(2-Hydroxyethyl)-N,4-dimethyl-3-oxopentanamide

0.351 mol (50 ml) of 4-methyl-3-oxovaleric acid methyl ester and 0.369mol (29.5 ml) 2-(methylamino)ethanol were stirred for 15 h at 120° C. ina Dean-Stark apparatus. 12 ml of methanol were collected. Subsequently,the excess starting materials 2 h were distilled off on a rotaryevaporator (80° C. water bath, 1 mbar). There were obtained 64 g of thetitle compound.

IR (neat, cm⁻¹): 2969, 2934, 2875, 1713, 1621, 1491, 1466, 1401, 1384,1358, 1303, 1265, 1211, 1120, 1072, 1048, 996, 926, 892, 862, 784, 726,692, 615.

CHN-Elemental analysis: C, 52.00; H, 6.84; N, 6.01.

LC-MS: M+H⁺, 188.7; M+Na⁺, 210.6.

¹H-NMR (DMSO-d₆, 400 MHz): E/Z-Isomerie im Verhältnis ca. 45/55;Enol-Tautomer (20%), δ [ppm]=5.31, 5.28 (s, 1H), 3.55-3.42 (m, 2H),3.42-3.25 (m, 2H), 3.0-2.8 (m, 3H), 2.4-2.3 (m, 1H), 1.07 (d, 6H);Keto-Tautomer (80%), δ=3.70, 3.66 (s, 2H), 3.55-3.42 (m, 2H), 3.42-3.25(m, 2H), 2.94, 2.83 (s, 3H), 2.71, 2.70 (heptett, 1H), 1.02, 1.01 (d,6H).

AAN. N,N,2-Trimethyl-3-oxobutanamide

0.318 mol (50 ml) of ethyl 2-methylacetoacetic acid ester (ethyl2-methyl-3-oxo-butanoate) (technical 90%) and 143 ml 33% dimethylaminein ethanol (about 0.795 mol dimethylamine) were stirred in a pressurereactor for 8 hours at 130° C. After cooling the reaction mixture wasconcentrated on a rotary evaporator, the residue was dissolved in 400 mlethyl acetate and extracted 5 times with 150 ml of water. The combinedwater phases were evaporated in a rotary evaporator to dryness. 18.8 gof the title compound were obtained.

IR (neat, cm⁻¹): 2984, 2938, 1721, 1632, 1497, 1451, 1396, 1355, 1312,1265, 1214, 1180, 1145, 1078, 1041, 952, 795, 770, 734, 689, 635, 623.

CHN-Elemental analysis: C, 71.21; H, 7.81; N, 6.39; O, 14.59.

LC-MS: M+H⁺, 144.6; M+Na⁺, 166.6.

¹H-NMR (DMSO-d₆, 400 MHz): 5 [ppm]=3.92 (q, 1H); 3.03 (s, 3H); 2.84 (s,3H); 2.06 (s, 3H); 1.12 (d, 3H).

AAO. N,N-Dimethyl-2-oxocyclohexancarboxamide

0.313 mol (50 ml) of ethyl cyclohexanone-2-carboxylate and 140 ml 33%dimethylamine in ethanol (about 0.78 mol dimethylamine) were stirred ina pressure reactor for 12 hours at 110° C. After cooling the reactionmixture was concentrated on a rotary evaporator, the residue wasdissolved in 500 ml ethyl acetate and the organic phase was washed with200 ml of 1 M NaOH and 3×50 ml water. The organic phase was thenevaporated on a rotary evaporator to dryness. 46 g of the crude productwas dissolved in 100 ml tert-butyl methyl ether and cooled to 0° C.Precipitated product was filtered off and dried, 3.6 g of the titlecompound were obtained.

IR (neat, cm⁻¹): 2939, 2867, 1691, 1639, 1496, 1454, 1442, 1429, 1409,1396, 1342, 1316, 1287, 1261, 1208, 1155, 1130, 1096, 1067, 1038, 1012,959, 923, 897, 870, 853, 808, 769, 696, 659, 623.

CHN-Elemental analysis: C, 71.21; H, 7.81; N, 6.39; O, 14.59.

LC-MS: M+H⁺, 170.6; M+Na⁺, 192.8.

¹H-NMR (DMSO-d₆, 400 MHz): δ [ppm]=3.86 (dd, 1H), 2.82 (s, 3H), 2.81 (s,3H), 2.54-2.22 (m, 2H), 2.0-1.5 (m, 6H).

AAP. N,N-Dimethyl-2-oxocyclopentancarboxamide

0.337 mol (50 ml) of ethyl 2-oxocyclopentanecarboxylate and 152 ml 33%dimethylamine solution in ethanol were stirred in a pressure reactor for4 h at 110° C. The reaction mixture was then evaporated to dryness andthe crude product was purified over 400 g silica gel with ethylacetate/hexane 1/1. 17.7 g of the title compound were obtained.

IR (neat, cm⁻¹): 2955, 2884, 1735, 1634, 1494, 1455, 1396, 1320, 1260,1198, 1167, 1140, 1101, 1059, 1025, 1004, 983, 946, 915, 904, 833, 752,689, 623.

LC-MS: M+H⁺, 156.7; M+Na⁺, 178.6.

1H-NMR (DMSO-d₆, 400 MHz): δ [ppm]=3.72 (t, 1H); 3.03 (s, 3H); 2.83 (s,3H); 2.3-1.4 (m, 6H).

AAQ. N-Cyclopentyl-3-oxobutanamide

A solution of 21.3 g (0.25 mol) cyclopentylamine in 50 mltetrahydrofuran was added dropwise at −5 to 0° C. to a solution of 20 gof diketene (0.24 mol) in 200 ml tetrahydrofuran. After 1 h stirring at0° C. no more starting material was detected by thin layerchromatography. The reaction mixture was evaporated and the residue isrecrystallized from 100 ml of ethyl acetate. This gave 31.4 g (0.19 mol,78% yield) as a white solid.

IR (neat, cm⁻¹): 3256, 3083, 2947, 2919, 2868, 1719, 1647, 1626, 1556,1422, 1357, 1197, 1161, 999.

LC-MS: 170 (M+H).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=6.9 (1H), 4.2 (1H), 3.3 (2H), 2.2 (3H),1.9 (2H), 1.6 (4H), 1.4 (2H).

AAR. 1-(Pyrrolidin-1-yl)butane-1,3-dione

A solution of 21 ml (0.25 mol) of pyrrolidine in 50 ml tetrahydrofuranwas added dropwise to a solution of 20 g of diketene (0.24 mol) in 200ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no morestarting material was detected by thin layer chromatography. Thereaction mixture was evaporated and the residue was purified by columnchromatography. This gave 29.9 g (0.19 mol, 81% yield) of an oil.

IR (neat, cm⁻¹): 2972, 2875, 1719, 1633, 1589, 1481, 1433, 1381, 1356,1226, 1193, 1159, 934, 776.

LC-MS: 156 (M+H), 178 (M+Na).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=3.2 (5H), 2.1 (3H), 1.7 (5H).

AAS. Methyl N-(3-oxobutanoyl)-L-serinate

10.8 g (0.13 mol) of diketene, 20 g L-serine methyl ester hydrochloride(0.13 mol) and 21.6 g (0.26 mol, 2 eq) of NaHCO₃ were mixed in 1000 mlof THF at 0° C. Then the ice bath was removed and it was stirred furtherat room temperature. After 24 h stirring at room temperature, thereaction mixture was filtered and the residue was recrystallized from100 ml of ethyl acetate. This gave 21.14 g (0.10 mol, 81% yield) as awhite solid.

IR (neat, cm⁻¹): 3499, 3297, 2962, 1734, 1712, 1642, 1556, 1430, 1416,1351, 1316, 1246, 1209, 1190, 1170, 1137, 1081, 1040, 978, 704.

LC-MS: 226 (M+Na), 187 (M−CH₃−H).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=8.4 (1H), 5.1 (1H), 4.4 (1H), 3.7 bis3.4 (7H), 2.1 (3H).

AAT. 1-(4-Acetylpiperazin-1-yl)butane-1,3-dione

A solution of 20.8 g (0.17 mol) 1-acetylpiperazine in 50 mltetrahydrofuran were added dropwise to a solution of 13 g of diketene(0.16 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirringat 0° C. no more starting material was detected by thin layerchromatography. The reaction mixture was evaporated and the residuepurified by column chromatography. This gave 27.2 g (0.13 mol, 83%yield) of a colorless oil.

IR (neat, cm⁻¹): 2919, 2864, 1718, 1631, 1422, 1358, 1307, 1284, 1248,1159, 1063, 993.

LC-MS: 213 (M+H), 235 (M+Na).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=3.6 (6H), 3.4 (3H), 3.3 (1H), 2.2 (3H),2.1 (3H).

AAU. N-Cyclohexyl-3-oxobutanamide

A solution of 23.6 g (0.24 mol) of cyclohexylamine in 50 mltetrahydrofuran was added dropwise to a solution of 20 g of diketene(0.24 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirringat 0° C. no more starting material was detected by thin layerchromatography. The reaction mixture was evaporated and the residue isrecrystallized from 100 ml of ethyl acetate. This gave 30.0 g (0.16 mol,69% yield) of a white solid.

IR (neat, cm⁻¹): 3259, 3088, 2929, 2852, 1716, 1648, 1627, 1560, 1449,1427, 1359, 1346, 1193, 1162, 1105, 1001, 892, 751, 718.

LC-MS: 184 (M+H), 206 (M+Na).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=6.9 (1H), 3.7 (1H), 3.3 (2H), 2.2 (3H),1.9 (2H), 1.7 (2H), 1.6 (1H), 1.2 (2H), 1.1 (3H).

AAV. Methyl N-(3-oxobutanoyl)glycinate

29.87 g (0.24 mol) of glycine methyl ester hydrochloride were added to asolution of 20.00 g (0.24 mol) of diketene in 250 ml toluene at 0° C.Then, 40.00 g (0.48 mol) NaHCO₃ were added and the reaction mixture wasstirred overnight at room temperature. Since thin-layer chromatographydetected no more starting material, the reaction mixture was filtered,evaporated and the residue purified by column chromatography. This gave33.4 g (0.19 mol, 81% yield) oil.

IR (neat, cm⁻¹): 3346, 1750, 1708, 1669, 1538, 1399, 1360, 1320, 1278,1198, 1165, 1024.

LC-MS: 174 (M+H), 196 (M+Na).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=7.5 (1H), 4.0 (2H), 3.7 (3H), 3.4 (2H),2.2 (3H).

AAW. N-(2-Methylpropyl)-3-oxobutanamide

A solution of 18.20 g (0.25 mol) isobutylamine in 50 ml tetrahydrofuranwas added dropwise to a solution of 20 g of diketene (0.24 mol) in 200ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no morestarting material was detected by thin layer chromatography. Thereaction mixture was evaporated and the residue is recrystallized from100 ml of ethyl acetate. This gave 26.93 g (0.17 mol, 72% yield) of awhite solid.

IR (neat, cm⁻¹): 3269, 3098, 2964, 2875, 1711, 1640, 1574, 1473, 1414,1355, 1328, 1271, 1190, 1160, 976, 823, 764, 727.

LC-MS: 158 (M+H), 180 (M+Na).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=7.1 (1H), 4.3 (2H), 3.1 (2H), 2.2 (3H),1.7 (1H), 0.9 (6H).

AAX. N-(Cyclopropylmethyl)-3-oxobutanamide

A solution of 15.1 g (0.22 mol) cyclopropylmethylamine in 50 mltetrahydrofuran was added dropwise to a solution of 17 grams of diketene(0.20 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirringat 0° C. no more starting material was detected by thin layerchromatography. The reaction mixture was evaporated and the residue isrecrystallized from 100 ml of ethyl acetate. This gave 19.7 g (0.13 mol,63% yield) of a white solid.

IR (neat, cm⁻¹): 3255, 3083, 3008, 2932, 1712, 1640, 1415, 1356, 1326,1276, 1191, 1160, 1079, 1017, 830, 800, 775, 729.

LC-MS: 156 (M+H), 178 (M+Na).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=7.0 (1H), 3.4 (2H), 3.1 (2H), 2.3 (3H),0.9 (1H), 0.5 (2H), 0.1 (2H).

AAY. Ethyl 4-(morpholin-4-yl)-2,4-dioxobutanoate

10.2 g of diisopropylamine (0.1 mol) was placed in 100 ml dry THF undernitrogen and cooled in a freezing mixture. 40 ml n-butyllithium inhexane (2.5 M, 0.1 mol) was slowly added dropwise. When the addition wascompleted the mixture was allowed to stir for 60 minutes and thenacetylmorpholine 12.9 g (0.1 mol) was added dropwise. The reactionmixture was stirred for 20 min in the freezing mixture. In a secondflask, 43.7 g of diethyl oxalate (0.3 mol) in 50 ml of dry THF wascooled in a freezing mixture and the cooled reaction mixture wascannulated with stirring in small portions to it. It was left overnightunder stirring to warm to room temperature. The THF was removed on arotary evaporator and the residue was taken up in 80 ml halfconcentrated hydrochloric acid. The aqueous phase was extracted fivetimes with 150 ml ethyl acetate, and the combined organic phases weredried over sodium sulfate and concentrated on a rotary evaporator todryness. The excess diethyl oxalate was removed by distillation (2-3mbar, 80° C.). 5.0 g of product were obtained in the form of whitecrystals with a melting point of 60° C. after crystallization from PE(petrol ether).

IR (neat, cm⁻¹): 2998, 2980, 2915, 2873, 1722, 1632, 1585, 1489, 1446,1396, 1375, 1271, 1236, 1136, 1113, 1072, 1054, 1019, 981, 917, 874,858, 837, 825, 766, 723, 639.

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=1.35 (3H), 3.50-3.73 (8H), 4.33 (2H),6.20 (1H), 14.32 (1H).

AAZ. Ethyl N-(3-oxobutanoyl)-L-alaninate

20.00 g (0.13 mol) of ethyl (2S)-2-aminopropanoate hydrochloride wereadded to a solution of 10.95 g (0.13 mol) of diketene in 500 ml tolueneat 0° C. Then, 21.90 g (0.26 mol) NaHCO₃ was added and the reactionmixture was stirred overnight at room temperature. Since no morestarting material was detected by thin-layer chromatography, thereaction mixture was filtered, evaporated and the residue purified bycolumn chromatography. This gave 19.36 g (0.096 mol, 74% yield) of acolorless oil.

IR (neat, cm⁻¹): 3308, 2985, 1720, 1647, 1537, 1453, 1360, 1205, 1155,1056, 1021.

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=7.4 (1H), 4.5 (1H), 4.1 (2H), 3.4 (2H),2.2 (3H), 1.3 (3H), 1.2 (3H).

ABA. N-Cyclobutyl-3-oxobutanamide

A solution of 20.00 g (0.28 mol) cyclobutylamine in 50 mltetrahydrofuran was added dropwise to a solution of 22.00 g of diketene(0.26 mole) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirringat 0° C. no more starting material was detected by thin layerchromatography. The reaction mixture was evaporated and the residue isrecrystallized from 100 ml of ethyl acetate. This gave 24.60 g (0.16mol, 61% yield) of a white solid.

IR (neat, cm⁻¹): 3251, 3080, 2974, 2949, 1721, 1649, 1626, 1554, 1423,1356, 1341, 1243, 1216, 1162, 994, 748, 717.

LC-MS: 156 (M+H), 178 (M+Na).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=7.2 (1H), 4.3 (1H), 3.3 (2H), 2.3 (5H),2.8 (2H), 2.6 (2H).

ABB. 1-(Azetidin-1-yl)-butane-1,3-dione

A solution of 18.00 g (0.31 mol) azetidine in 50 ml tetrahydrofuran wasadded dropwise to a solution of 25.00 g of diketene (0.30 mol) in 200 mltetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no morestarting material was detected by thin layer chromatography. Thereaction mixture was evaporated and the residue is recrystallized from100 ml of ethyl acetate. This gave 26.45 g (0.19 mol, 63% yield) of awhite solid.

IR (neat, cm⁻¹): 3107, 2983, 2958, 2885, 1718, 1631, 1462, 1443, 1410,1367, 1306, 1298, 1237, 1188, 1168, 1154, 1112, 1014, 851, 736.

LC-MS: 142 (M+H), 164 (M+Na).

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=4.1 (2H), 3.9 (2H), 3.1 (2H), 2.1 (5H).

ABC. Ethyl 1-(3-oxobutanoyl)-piperidine-4-carboxylate

A solution of 18.70 g (0.12 mol) ethyl 4-piperidinecarboxylate in 50 mltetrahydrofuran was added dropwise to a solution of 10.00 g of diketene(0.12 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirringat 0° C. no more starting material was detected by thin layerchromatography. The reaction mixture was evaporated and the residuepurified by column chromatography.

This gave 19.52 g (0.081 mol, 68% yield) of a colorless oil.

IR (neat, cm⁻¹): 2957, 2932, 2863, 1721, 1634, 1446, 1314, 1272, 1250,1173, 1158, 1110, 1097, 1039, 939.

¹H-NMR (CDCl₃, 400 MHz): δ [ppm]=4.3 (1H), 4.1 (2H), 3.7 (1H), 3.5 (2H),3.1 (1H), 2.9 (1H), 2.5 (1H), 2.2 (3H), 1.9 (2H), 1.6 (2H), 1.2 (3H).

ABD. 1-(4-Hydroxypiperidin-1-yl)-4-methoxybutane-1,3-dione

0.34 mol (48.7 g) of methyl 4-methoxy-acetoacetate and 0.36 mol (36.0 g)of 4-hydroxypiperidine were stirred for 5 h at 120° C. at a Dean-Starkapparatus. 45 g of the crude product was purified over 1 kg of silicagel with ethyl acetate/ethanol 9/1. 23.7 g of the title compound wereobtained.

IR (neat, cm⁻¹): 2931, 1729, 1618, 1448, 1365, 1310, 1266, 1201, 1132,1101, 1072, 1025, 977, 935, 809, 776, 716, 681.

LC-MS: M+H⁺, 216.8; M+Na⁺, 238.7.

¹H-NMR (DMSO-d₆, 400 MHz): Enol-Tautomer (14%), δ [ppm]=15.10 (s, 1H),5.56 (s, 1H), 4.76 (d (J=4 Hz), 1H), 3.90 (s, 2H), 3.9-2.9 (m, 5H), 3.29(s, 3H), 1.8-1.1 (m, 4H); Keto-Tautomer (86%), δ [ppm]=4.73 (d (J=4 Hz),1H), 4.10 (s, 2H), 3.9-2.9 (m, 5H), 3.57 (s, 2H), 3.27 (s, 3H), 1.8-1.1(m, 4H).

Testing Method:

The excellent Fe utilizations that can be accomplished through the Fecomplexes according to the invention were measured by means of thefollowing mouse model.

Male NMRI (SPF) mice (approximately 3 weeks old) were fed a low-irondiet (approx. 5 ppm iron) for approximately 3 weeks. The iron complexeswere then administered to them by means of a stomach tube (2 mg iron/kgbody weight/day) for 2 times 5 days, with an interruption of 2 days(days 1-5 and 8-12). Utilization on day 15 was calculated from thehemoglobin increase and the body weight increase in accordance with theformula

${\left. {{{Utilization}\mspace{14mu}(\%)} = {\frac{\Delta\mspace{14mu}{iron}\mspace{14mu}{utilization}*100}{{Fe}\mspace{14mu}{{Dos}.}} = {\frac{\left( {{Fe}\mspace{14mu}{{ut}.{- {Fe}}}\mspace{14mu}{{ut}.\mspace{14mu}{Control}}} \right)*100}{{Fe}\mspace{14mu}{{Dos}.}} = \left\lbrack {{\left( {{{Hb}_{2{(3)}}*{BW}_{9{(14)}}} - {{Hb}_{1}*{BW}_{4}}} \right)*0.07*0.0034} - {\left( {{{Hb}_{2{(3)}\mspace{11mu}{Control}}*{BW}_{9{(14)}\mspace{11mu}{Control}}} - {{Hb}_{1\mspace{11mu}{Control}}*{BW}_{4\mspace{11mu}{Control}}}} \right)*0.07*0.0034}} \right)}}} \right\rbrack*{100/{Fe}}\mspace{14mu}{{Dos}.}} = {{\left\lbrack {{\left( {{{Hb}_{2{(3)}}*{BW}_{9{(14)}}} - {{Hb}_{1}*{BW}_{4}}} \right)*0.000238} - {\left( {{{Hb}_{2{(3)}\mspace{11mu}{Control}}*{BW}_{9{(14)}\mspace{11mu}{Control}}} - {{Hb}_{1\mspace{11mu}{Control}}*{BW}_{4\mspace{11mu}{Control}}}} \right)*0.000238}} \right\rbrack*{100/{Fe}}\mspace{14mu}{{Dos}.}} = {\left( {{{Hb}_{2{(3)}}*{BW}_{9{(14)}}} - {{Hb}_{1}*{BW}_{4}} - {{Hb}_{2{(3)}\mspace{11mu}{Control}}*{BW}_{9{(14)}\mspace{11mu}{Control}}} + {{Hb}_{1\mspace{11mu}{Control}}*{BW}_{4\mspace{11mu}{Control}}}} \right)*{0.0238/{Fe}}\mspace{14mu}{{Dos}.}}}$0.07=Factor for 70 ml blood per kg body weight (BW)0.0034=Factor for 0.0034 g Fe/g HbHb₁=Hemoglobin level (g/l) on day 1Hb₂₍₃)=Hemoglobin level (g/l) on day 8 (or 15)BW₄=body weight (g) on day 1BW₉₍₁₄₎=body weight (g) on day 8 (or 15)Hb_(1 Control)=average hemoglobin level (g/l) on day 1 in the controlgroup,Hb_(2(3) Control)=average hemoglobin level (g/l) on day 8 (or 15) in thecontrol group,BW_(4 Control)=average body weight (g) on day 1 in the control group,BW_(9(14) Control)=average body weight (g) on day 8 (or 15) in thecontrol group,Fe Dos.=entire administered iron (mg Fe) over 5 or 10 days,Fe ut.=(Hb₂₍₃)*BW₉₍₁₄₎−Hb₁*BW₄)*0.07*0.0034 (mg Fe)ΔUtilization=Fe tot. utilized (examined group)−Fe ut. Control group,utilized from food, (mg Fe)

TABLE Utilization n 15 d Example-No. (abs. %) 1 61 2 41 3 95 4 90 5 61 657 7 41 8 69 9 54 10 45 11 75 12 35 13 71 14 68 15 68 16 60 17 48 18 8119 73 20 77 21 — 22 78 23 88 24 70 25 60 26 64 27 88 28 73 29 79 30 — 3171 32 81 33 69 34 32 35 44 36 79 37 34 38 77 39 66 40 87 41 68 42 30 4375 44 73 45 — 46 78 47 61 48 53 49 — 50 — 51 78 52 84 53 — 54 76 55 8456 — 57 — 58 — 59 80 60 80 61 73 62 68 63 71 64 79 65 73 66 — “—” means:not determined.

PREPARATION EXAMPLES Example 1 Tris-(3-oxobutaneamide)-iron(III) complex

A solution of 24.00 g (0.15 mol) iron(III) chloride (anhydrous) in 400ml ethanol was added dropwise to a solution of 45.00 g (0.45 mol)3-oxobutaneamide in 400 ml ethanol. 37.46 g (0.45 mol) sodiumbicarbonate was then added in portions. After 4 hours of stirring atroom temperature, the reaction mixture was filtrated off, the filtratespun off and the residue dried overnight in the drying cabinet at 50° C.51.63 g of product was obtained as a black-red solid.

IR (in substance, cm⁻¹): 3317, 3187, 1618, 1569, 1507, 1415, 1328, 1194,1092, 1034, 978, 935, 780.

Elemental analysis: C, 37.41; H, 5.78; N, 8.80.

Fe content 15.80% [m/m].

Example 2 Tris-(N,N-diethyl-3-oxobutaneamide)-iron(III) complex

A solution of 1.00 g (6.17 mmol) iron(III) chloride (anhydrous) in 10 mlethanol was added dropwise to a solution of 2.90 g (18.50 mmol)N,N-diethyl-3-oxobutaneamide in 30 ml ethanol. 3.11 g (37.00 mmol)sodium bicarbonate was then added in portions. After 2 hours of stirringat room temperature, the reaction mixture was filtrated off, thefiltrate spun off and the residue dried overnight in the drying cabinetat 50° C. 3.50 g of product was obtained as a black-red oil.

IR (in substance, cm⁻¹): 2973, 2932, 1597, 1557, 1511, 1492, 1454, 1434,1374, 1356, 1309, 1274, 1204, 1163, 1082, 1004, 962.

Elemental analysis: C, 53.54; H, 8.00; N, 7.88.

Fe content 9.63% [m/m].

Example 3 Tris-(N,N-dimethyl-3-oxobutaneamide)-iron(III) complex

A solution of 3.00 g (18.50 mmol) iron(III) chloride (anhydrous) in 50ml ethanol was added dropwise to a solution of 8.96 g (55.50 mmol, 80%in water) N,N-dimethyl-3-oxobutaneamide in 50 ml ethanol. 4.66 g (55.50mmol) sodium bicarbonate was then added in portions. After 4 hours ofstirring at room temperature, the reaction mixture is filtrated off,washed with 10 ml EtOH, the filtrate spun off and the residue driedovernight in the drying cabinet at 50° C. 8.37 g of product was obtainedas a black-red oil.

IR (in substance, cm⁻¹): 2918, 1720, 1643, 1557, 1523, 1490, 1433, 1401,1347, 1260, 1211, 1177, 1061, 1032, 989, 955.

Elemental analysis: C, 47.39; H, 6.70; N, 9.22.

Fe content 11.13% [m/m].

Example 4 Tris-(N-methyl-3-oxobutaneamide)-iron(III) complex

A solution of 3.00 g (18.50 mmol) iron(III) chloride (anhydrous) in 50ml ethanol was added dropwise to a solution of 9.13 g (55.50 mmol, 80%in water) N-methyl-3-oxobutaneamide in 50 ml ethanol. 4.66 g (55.50mmol) sodium bicarbonate was then added in portions. After 2 hours ofstirring at room temperature, the reaction mixture was filtrated off,washed with 10 ml EtOH, the filtrate spun off and the residue driedovernight in the drying cabinet at 50° C. 7.98 g of product was obtainedas a black-red solid.

IR (in substance, cm⁻¹): 3336, 3119, 2913, 1558, 1500, 1448, 1411, 1275,1191, 1157, 1104, 1010, 959, 935, 779.

Elemental analysis: C, 42.23; H, 5.78; N, 9.70.

Fe content 12.46% [m/m].

Example 5 Tris(3-oxo-2-(piperidin-1-ylcarbonyl)butanenitrile)-iron(III)complex

1.4 g (8.5 mmol) FeCl₃ (anhydrous) dissolved in 20 ml ethanol 99% wereadded to a solution of 5.0 g (25.7 mmol) 2,4-dioxo-3-cyanobutylpiperidinin 40 ml EtOH 99%. 2.2 g (25.6 mmol) NaHCO₃ were then added and this wasfollowed by stirring for 1 hour at 20-25° C. The reaction mixture isfiltrated, the filtrate concentrated to dryness on the rotavap at 50°C./<100 mbar, and the residue was dried in the vacuum drying cabinet forat least 15 hours at 50° C./<100 mbar. The obtained solid was suspendedin 200 ml water for approx. 30 min with an Ultraturax, filtrated off andagain dried in the vacuum drying cabinet for at least 15 hours at 50°C./<100 mbar. 5.3 g of product was obtained as an orange solid.

IR (in substance, cm⁻¹): 2936, 2858, 2197, 1594, 1532, 1506, 1439, 1387,1270, 1217, 1169, 1145, 1072, 1020, 973, 905, 854, 755, 700, 653.

Elemental analysis: C, 57.0; H, 6.40; N, 12.60.

Fe content 8.30% [m/m].

Example 6 Tris-(2-chloro-N-methyl-3-oxobutaneamide)-iron(III) complex

A solution of 1.00 g (6.17 mmol) iron(III) chloride anhydrous in 10 mlethanol was added dropwise to a solution of 2.77 g (18.50 mmol)2-chloro-N-methyl-3-oxobutaneamide in 30 ml ethanol. 1.55 g (18.50 mmol)sodium bicarbonate was then added in portions. After 2 hours of stirringat room temperature, the reaction mixture was filtrated off, washed with10 ml EtOH, the filtrate spun off and the residue dried overnight in thedrying cabinet at 50° C. 3.19 g of product was obtained as a violetsolid.

IR (in substance, cm⁻¹): 3359, 2942, 1545, 1468, 1406, 1375, 1260, 1155,1118, 1028, 935, 796, 748.

Elemental analysis: C, 33.42; H, 4.23; N, 7.74.

Fe content 10.72% [m/m].

Example 7 Tris(N-butyl-3-oxobutaneamide)-iron(III) complex

1.4 g (8.6 mmol) FeCl₃ (anhydrous) dissolved in 10 ml methanol wereadded to a solution of 5 g (31.8 mmol) N-n-butyl-3-oxo-butaneamide in 40ml toluene. 4.4 g (52.4 mmol) NaHCO₃ and 2.2 g (15.5 mmol) Na₂SO₄(anhydrous) were then added and this was followed by stirring for 1 hourat 20-25° C. The reaction mixture was filtrated, the filtrateconcentrated to dryness on the rotavap at 50° C./<100 mbar, and theresidue was dried in the vacuum drying cabinet for at least 15 hours at50° C./<100 mbar. 5.0 g of product was obtained as a red solid.

IR (in substance, cm⁻¹): 2935, 1645, 1592, 1533, 1508, 1439, 1387, 1270,1219, 1143, 1073, 1020, 973, 909, 855, 822, 699, 652.

Fe content 9.0% [m/m].

Example 8 Tris(N,N-dibutyl-3-oxobutaneamide)-iron(III) complex

48.5 g (0.23 mol) N,N-dibutyl-3-oxo-butaneamide and 20.6 g (0.08 mol)FeCl₃×6H₂O were provided in 245 ml ethanol 96%. 14.1 g (0.13 mol) Na₂CO₃(anhydrous) was added in several portions within approx. 5 min. Thereaction container is cooled in the process with a water bath of approx.20° C. The reaction mixture was stirred for 6 hours at 20-25° C.,subsequently filtrated over a glass frit and concentrated to dryness onthe rotavap at 50° C./<100 mbar. The oily product was dried for at least15 hours at 20-25° C. under a high vacuum. 50 g of product was obtainedas a red-brown oil.

IR (in substance, cm⁻¹): 2957, 2931, 2872, 1596, 1558, 1513, 1492, 1461,1431, 1366, 1292, 1257, 1229, 1199, 1155, 1112, 1007, 956, 764.

CHN elemental analysis: C, 61.10; H, 9.60; N, 6.00.

Fe content 8.00% [m/m].

Example 9 Tris-(1-(piperidin-1-yl)-butane-1,3-dione)-iron(III) complex

A solution of 1.00 g (6.17 mol) iron(III) chloride (anhydrous) in 10 mlethanol was added dropwise to a solution of 3.13 g (18.50 mmol)1-(piperidin-1-yl)-butane-1,3-dione in 40 ml ethanol. 6.26 g (74.00mmol) sodium bicarbonate was then added in portions. After 2 hours ofstirring at room temperature, the reaction mixture was filtrated off,washed with 10 ml EtOH, the filtrate spun off and the residue driedovernight in the drying cabinet at 50° C. 3.72 g of product was obtainedas a black oil.

IR (in substance, cm⁻¹): 2930, 2852, 1594, 1556, 1509, 1483, 1461, 1442,1374, 1347, 1256, 1231, 1205, 1022, 958.

Elemental analysis: C, 55.33; H, 7.49; N, 7.01.

Fe content 9.30% [m/m].

Example 10 Tris(3-oxoheptaneamide)-iron(III) complex

15 mmol (2.147 g) 3-oxoheptaneamide were dissolved in 50 ml ethanol(anhydrous) in a 100 ml Erlenmeyer flask with a drying tube, and 5 mmol(0.811 g) FeCl₃ (anhydrous) was added. 20 mmol (1.68 g) NaHCO₃ was addedafter 5 min and stirring was continued for another 2 hours. pHmonitoring showed pH 3.78 after 2 hours (sample was filtrated anddiluted with water; pH 2.78 after 0.5 hours; 3.19 after 1 hour; 3.56after 1.5 hours). The reaction mixture was filtrated, the filtrate wasconcentrated on the rotavap and the product was dried under an oil pumpvacuum. 2.25 g of product was obtained.

IR (in substance, cm⁻¹): 3318, 3195, 2956, 2930, 2870, 1715, 1617, 1564,1507, 1458, 1355, 1192, 1093, 946, 780, 663.

Elemental analysis: C, 49.06; H, 7.45; N, 8.28.

Fe content 10.91% [m/m].

Example 11 Tris(N-methyl-3-oxoheptaneamide)-iron(III) complex

8.3 mmol (1.37 g) 3-oxoheptanoic acid methylamide were dissolved in 40ml ethanol (anhydrous) in a 100 ml Erlenmeyer flask with a drying tube,and 2.8 mmol (0.447 g) FeCl₃ (anhydrous) was added. 11 mmol (0.927 g)NaHCO₃ was added, followed by stirring for 2.5 hours. pH monitoringshowed pH 3.8 after 2.5 hours (sample was filtrated and diluted withwater). The reaction mixture was filtrated, the filtrate wasconcentrated on the rotavap and the product was dried at 50° C. in thevacuum drying cabinet. 1.20 g of product was obtained.

IR (in substance, cm⁻¹): 3283, 3117, 2956, 2932, 2871, 1718, 1561, 1502,1420, 1377, 1271, 1157, 1108, 1082, 967, 937, 886, 779, 649.

Elemental analysis: C, 52.2; H, 7.65; N, 7.61.

Fe content 9.14% [m/m].

Example 12 Tris-(N,N-bis-(2-hydroxyethyl)-3-oxobutaneamide)-iron(III)complex

A solution of 1.00 g (6.17 mmol) iron(III) chloride (anhydrous) in 10 mlethanol was added dropwise to a solution of 3.50 g (18.50 mmol)N,N-bis-(2-hydroxyethyl)-3-oxobutaneamide in 30 ml ethanol. 1.56 g(18.50 mmol) sodium bicarbonate was then added in portions. After 4hours of stirring at room temperature, the reaction mixture wasfiltrated off, washed with 10 ml EtOH, the filtrate spun off and theresidue dried overnight in the drying cabinet at 50° C. 4.19 g ofproduct was obtained as a black oil.

IR (in substance, cm⁻¹): 3327, 2974, 2934, 2880, 1632, 1567, 1516, 1494,1438, 1361, 1301, 1228, 1206, 1170, 1052.

Elemental analysis: C, 43.61; H, 7.46; N, 5.34.

Fe content 8.14% [m/m].

Example 13 Tris-(N-butyl-N-methyl-3-oxobutaneamide)-iron(III) complex

A solution of 0.50 g (3.08 mmol) iron(III) chloride (anhydrous) in 5 mlethanol was added dropwise to a solution of 1.58 g (9.25 mmol)N-n-butyl-N-methyl-3-oxobutyramide in 15 ml ethanol. 0.78 g (9.25 mmol)sodium bicarbonate was then added in portions. After 4 hours of stirringat room temperature, the reaction mixture was filtrated off, washed with10 ml EtOH, the filtrate spun off and the residue dried overnight in thedrying cabinet at 50° C. 1.80 g of product was obtained as a black oil.

IR (in substance, cm⁻¹): 2956, 2930, 2871, 1598, 1557, 1515, 1492, 1464,1353, 1308, 1230, 1211, 1088, 957.

Elemental analysis: C, 55.26; H, 8.25; N, 7.21.

Fe content 9.36% [m/m].

Example 14 Tris-(1-(4-hydroxypiperidin-1-yl)-butane-1,3-dione)-iron(III)complex

A solution of 1.00 g (6.17 mol) iron(III) chloride (anhydrous) in 10 mlethanol was added dropwise to a solution of 3.43 g (18.51 mmol)1-(4-hydroxypiperidin-1-yl)-butane-1,3-dione in 30 ml ethanol. 3.11 g(37.00 mmol) sodium bicarbonate was then added in portions. After 4hours of stirring at room temperature, the reaction mixture wasfiltrated off, washed with 10 ml EtOH, the filtrate spun off and theresidue dried overnight in the drying cabinet at 50° C. 3.98 g ofproduct was obtained as a brown solid.

IR (in substance, cm⁻¹): 3334, 2923, 2859, 1589, 1554, 1509, 1485, 1443,1362, 1265, 1227, 1205, 1054, 1023, 954.

Elemental analysis: C, 51.47; H, 7.26; N, 6.37.

Fe content 8.28% [m/m].

Example 15 Tris-(3-oxo-N,N-dipropylbutaneamide)-iron(III) complex

A solution of 0.50 g (3.08 mmol) iron(III) chloride (anhydrous) in 5 mlethanol was added dropwise to a solution of 1.71 g (9.25 mmol)3-oxo-N,N-di-n-propylbutaneamide in 20 ml ethanol. 1.56 g (18.50 mmol)sodium bicarbonate was then added in portions. After 2 hours of stirringat room temperature, the reaction mixture was filtrated off, washed with10 ml EtOH, the filtrate spun off and the residue dried overnight in thedrying cabinet at 50° C. 1.94 g of product was obtained as a brown oil.

IR (in substance, cm⁻¹): 2962, 2931, 2874, 1597, 1557, 1510, 1491, 1468,1456, 1431, 1367, 1299, 1246, 1202, 1164, 1102, 1058, 996, 958.

Elemental analysis: C, 56.93; H, 8.73; N, 6.50.

Fe content 8.15% [m/m].

Example 16 Tris-(N-hexyl-3-oxobutaneamide)-iron(III) complex

A solution of 1.00 g (6.17 mmol) iron(III) chloride (anhydrous) in 5 mlethanol was added dropwise to a solution of 3.43 g (18.50 mmol)N-n-hexyl-3-oxobutaneamide in 25 ml ethanol. 3.12 g (37.00 mmol) sodiumbicarbonate was then added in portions. After 4 hours of stirring atroom temperature, the reaction mixture was filtrated off, washed with 10ml EtOH, the filtrate spun off and the residue dried overnight in thedrying cabinet at 50° C. 3.86 g of product was obtained as a brown oil.

IR (in substance, cm⁻¹): 3289, 2956, 2926, 2857, 1719, 1656, 1589, 1556,1503, 1453, 1434, 1410, 1274, 1188, 1037, 1017, 960, 946.

Fe content 8.34% [m/m].

Example 17 Tris(N,N-dimethyl-3-oxoheptaneamide)-iron(III) complex

In analogy to the preceding examples, thetris(N,N-dimethyl-3-oxoheptaneamide)-iron(III) complex was preparedstarting with iron(III) chloride and 3-oxo-heptanoic acid dimethylamide.

Example 18 Tris(3-oxopentaneamide)-iron(III) complex

15.0 mmol (1.73 g) 3-oxopentaneamide were dissolved in 100 ml ethanol(anhydrous) in a 250 ml round-bottomed flask with a drying tube, and 5.0mmol (0.811 g) FeCl₃ (anhydrous) was added. 20 mmol (1.68 g) NaHCO₃ wasadded, followed by stirring for 3 hours. pH monitoring showed pH 5.2(sample was filtrated and diluted with water). The reaction mixture wasfiltrated, the filtrate was concentrated on the rotavap and the productwas dried at 50° C. in the vacuum drying cabinet. 2.1 g of product wasobtained.

IR (in substance, cm⁻¹): 3318, 3189, 2974, 2938, 2361, 1715, 1625, 1567,1509, 1458, 1341, 1299, 1242, 1184, 1107, 1077, 1020, 952, 917, 804,785.

Elemental analysis: C, 39.86; H, 5.821; N, 9.28.

Fe content 11.85% [m/m].

Example 19 Tris(N,N-dimethyl-3-oxopentaneamide)-iron(III) complex

15.0 mmol (2.15 g) N,N-dimethyl-3-oxopentaneamide were dissolved in 75ml ethanol (anhydrous) in a 100 ml round-bottomed flask with a dryingtube, and 5.0 mmol (0.811 g) FeCl₃ (anhydrous) was added. 20 mmol (1.68g) NaHCO₃ was added, followed by stirring for 1.5 hours. pH monitoringshowed pH 4.2 (sample was filtrated and diluted with water). Thereaction mixture was filtrated, the filtrate was concentrated on therotavap and the product was dried at 50° C. in the vacuum dryingcabinet. 2.4 g of product was obtained.

IR (in substance, cm⁻¹): 2965, 2933, 2871, 2362, 1720, 1596, 1553, 1526,1492, 1428, 1402, 1371, 1352, 1311, 1259, 1197, 1175, 1061, 1020, 983,932, 835, 798, 766, 718, 688.

Elemental analysis: C, 50.35; H, 7.307; N, 8.31.

Fe content 10.50% [m/m].

Example 20 Tris-(ethyl N-(3-oxobutanoyl)glycinate)-iron(III) complex(Tris((3-Oxo-butyrylamino)ethyl acetate)iron)

A solution of 0.50 g (3.08 mmol) iron(III) chloride (anhydrous) in 5 mlethanol was added dropwise to a solution of 1.73 g (9.25 mmol) ethylN-(3-oxobutanoyl)glycinate (or. (3-oxo-butyrylamino)ethyl acetate,respectively) in 20 ml ethanol. 1.56 g (18.50 mmol) sodium bicarbonatewas then added in portions. After 2 hours of stirring at roomtemperature, the reaction mixture was filtrated off, washed with 10 mlEtOH, the filtrate spun off and the residue dried overnight in thedrying cabinet at 50° C. 2.11 g of product was obtained as a brown oil.

IR (in substance, cm⁻¹): 3304, 2982, 2936, 1736, 1661, 1586, 1543, 1497,1453, 1411, 1374, 1284, 1184, 1134, 1051, 1026.

Elemental analysis: C, 44.14; H, 6.11; N, 6.18.

Fe content 8.47% [m/m].

Example 21 Tris-(N,N-Dibutyl-3-oxopentanamide)-iron(III)-complex

18 mmol (4.09 g) N,N-dibutyl-3-oxopentanamide were dissolved in 90 mlethanol (anhydrous) and 6 mmol (0.811 g), FeCl₃ (anhydrous) was added.Then 5.93 ml sodium ethylate solution (21% m/m, about 18 mmol sodiumethylate) was added and it was stirred for 1 hour. The reaction mixturewas filtered and the filtrate was concentrated on a rotary evaporator.The residue was dissolved in 120 ml dichloromethane, filtered again, thefiltrate was evaporated and the product was dried in a vacuum oven at50° C. This gave 4.0 g of the title compound.

IR (neat, cm⁻¹): 2957, 2931, 2872, 2359, 1721, 1634, 1596, 1556, 1513,1491, 1461, 1429, 1393, 1366, 1316, 1291, 1254, 1225, 1190, 1155, 1112,1079, 1062, 990, 926, 799, 767, 733, 711, 657.

CHN-Elemental analysis: C, 62.57; H, 9.64; N, 5.66.

Fe-content: 7.3% [m/m]

Example 22Tris-(2-Fluoro-N,N-dimethyl-3-oxobutanamide)-iron(III)-complex

15 mmol (2.32 g) 2-fluoro-N,N-dimethyl-3-oxobutanamide were dissolved in125 ml ethanol (anhydrous), and 4.86 ml sodium ethylate solution (21%m/m, about 15 mmol sodium ethoxide) were added. Then 5 mmol (0.811 g),FeCl₃ (anhydrous) was added and is was stirred for 2 h at 50° C. Thereaction mixture was filtered after cooling, the filtrate wasconcentrated on a rotary evaporator and the product was dried in avacuum oven at 50° C. This gave 2.5 g of the title compound.

IR (neat, cm⁻¹): 2937, 2361, 2341, 1737, 1656, 1573, 1477, 1419, 1402,1361, 1332, 1259, 1209, 1145, 1051, 1020, 977, 894, 870, 736.

CHN-Elemental analysis: C, 38.59; H, 5.23; N, 7.15.

Fe-content: 9.96% [m/m]

Example 23 Tris-(2-Fluoro-3-oxo-N-propylbutanamide)-iron(III)-complex

18 mmol (2.9 g) 2-fluoro-3-oxo-N-propylbutanamide and 6 mmol (0.972 g)FeCl₃ (anhydrous) were dissolved in 90 ml ethanol (anhydrous), and 2.78ml sodium methylate solution (30% m/m, about 15 mmol sodium methoxide)were added. It was stirred for another 1 h, and the reaction solutionwas filtered. The filtrate was concentrated on a rotary evaporator andthe product was dried in a vacuum oven at 50° C. This gave 3.14 g of thetitle compound.

IR (neat, cm⁻¹): 3306, 3090, 2966, 2936, 2876, 1736, 1674, 1602, 1549,1522, 1459, 1438, 1382, 1275, 1246, 1160, 1114, 1088, 1050, 992, 958,899, 821, 774, 744, 645.

CHN-Elemental analysis: C, 44.36; H, 6.08; N, 7.22.

Fe-content: 9.34% [m/m]

Example 24Tris-(4-Methoxy-N,N-dimethyl-3-oxobutanamide)-iron(III)-complex

57 mmol (9.1 g) of 4-methoxy-N,N-dimethyl-3-oxobutanamide and 19 mmol(3.08 g) FeCl₃ (anhydrous) were dissolved in 260 ml ethanol (anhydrous),and 9.84 ml of sodium methoxide solution (30% m/m, about 53 mmol sodiummethoxide) was added. It was stirred for another 1 h and the reactionsolution was filtered. The filtrate was concentrated on a rotaryevaporator and the product was dried in a vacuum oven at 50° C. Thisgave 10.5 g of the title compound.

IR (neat, cm⁻¹): 2930, 2822, 1730, 1603, 1568, 1497, 1424, 1402, 1368,1331, 1260, 1200, 1174, 1109, 1059, 1023, 992, 959, 924, 862, 769, 736,681.

CHN-Elemental analysis: C, 44.94; H, 6.66; N, 7.06.

Fe-content: 9.49% [m/m]

Example 25 Tris-(N,N,4-Trimethyl-3-oxopentanamide)-iron(III)-complex

16 mmol (2.36 g) N,N,4-trimethyl-3-oxopentanamide and 5 mmol (0.811 g),FeCl₃ (anhydrous) were dissolved in 100 ml ethanol (anhydrous), and 2.78ml sodium methoxide solution (30% m/m, about 15 mmol sodium methoxide)were added. It was stirred for another 1 h and the reaction solution wasfiltered. The filtrate was concentrated on a rotary evaporator and theproduct was dried in a vacuum oven at 50° C. This gave 2.6 g of thetitle compound.

IR (neat, cm⁻¹): 2958, 2927, 2868, 1720, 1593, 1556, 1526, 1502, 1487,1402, 1378, 1359, 1311, 1260, 1198, 1176, 1157, 1083, 1006, 946, 891,801, 773, 722, 678, 655.

CHN-Elemental analysis: C, 52.88; H, 7.91; N, 7.50.

Fe-content: 10.40% [m/m]

Example 26Tris-(4-Methyl-1-(morpholin-4-yl)-pentane-1,3-dione)-iron(III)-complex

18 mmol (3.59 g) of 4-methyl-1-(morpholin-4-yl)pentane-1,3-dione and 6mmol (0.973 g) FeCl₃ (anhydrous) were dissolved in 50 ml ethanol(anhydrous) and 3.00 ml sodium methylate solution (30% m/m, about 16mmol sodium methylate) was added. It was stirred for another 1 h and thereaction solution was filtered. The filtrate was concentrated on arotary evaporator and the product was dried in a vacuum oven at 50° C.This gave 4.0 g of the title compound.

IR (neat, cm⁻¹): 2964, 2924, 2857, 1714, 1678, 1640, 1549, 1516, 1478,1459, 1439, 1384, 1371, 1357, 1313, 1300, 1273, 1244, 1189, 1159, 1114,1087, 1065, 1018, 990, 947, 885, 851, 773, 717, 680.

CHN-Elemental analysis: C, 48.70; H, 6.84; N, 6.01.

Fe-content: 7.89% [m/m]

Example 27Tris-(4-Methoxy-1-(morpholin-4-yl)butane-1,3-dione)-iron(III)-complex

15 mmol (3.02 g) of 4-methoxy-1-(morpholin-4-yl)butane-1,3-dione and 5mmol (0.811 g) FeCl₃ (anhydrous) were dissolved in 65 ml ethanol(anhydrous) and 2.59 ml sodium methylate solution (30% m/m, about 14mmol sodium methylate) was added. It was stirred for another 1 h and thereaction solution was filtered. The filtrate was concentrated on arotary evaporator and the product was dried in a vacuum oven at 50° C.This gave 3.66 g of the title compound.

IR (neat, cm⁻¹): 2969, 2897, 2856, 1732, 1640, 1597, 1563, 1514, 1441,1383, 1301, 1273, 1246, 1197, 1110, 1065, 1017, 992, 961, 922, 863, 765,730, 676.

CHN-Elemental analysis: C, 47.62; H, 6.90; N, 5.44.

Fe-content: 7.13% [m/m]

Example 28 Tris-(3-acetyl-1-methylpyrrolidin-2-one)-iron(III)-complex

2.48 g (15.30 mmol) of iron(III)-chloride were dissolved in 700 ml ofethanol and 6.91 g (49.00 mmol) of 3-acetyl-1-methylpyrrolidine-2-onewas added. 9.76 g 25% sodium methanolate solution (45.17 mmol) werediluted with 80 ml ethanol and added dropwise to the iron(III)-chloridesolution. The reaction solution was stirred for 30 min and then filteredoff. The filtrate was concentrated on a rotary evaporator to dryness andthe residue is dried overnight at 50° C. under vacuum. This gave 7.4 gproduct as a violet powder.

IR (neat, cm⁻¹): 2915, 2866, 1677, 1601, 1553, 1497, 1476, 1443, 1401,1365, 1344, 1267, 1182, 996, 964, 908, 746, 612.

Fe-content: 11.74% [m/m].

Example 29 Tris-(Ethyl(1-methyl-2-oxopyrrolidin-3-yl)(oxo)acetate)-iron(III)-complex

9.72 g of an iron ethoxide solution (2.22% Fe [m/m], 3.86 mmol) inethanol were diluted in a nitrogen atmosphere with 40 ml of dry ethanol.2.30 g (11.55 mmol) of ethyl (1-methyl-2-oxopyrrolidin-3-yl)(oxo)acetatewere added to the solution and stirred at room temperature overnight.Then the solution was evaporated in a rotary evaporator to dryness andthe residue dried at 50° C. overnight under vacuum. This gave 2.6 gproduct as a red solid.

IR (neat, cm⁻¹): 2933, 2896, 1719, 1704, 1607, 1500, 1477, 1455, 1407,1395, 1367, 1350, 1303, 1270, 1207, 1170, 1107, 1031, 1008, 914, 869,780, 743, 718, 633.

Elemental analysis: C, 47.90% H, 5.43% N, 6.11%.

Fe-content: 8.48% [m/m].

Example 30 Tris-(ethyl(1-methyl-2-oxopiperidin-3-yl)(oxo)acetate)-iron(III)-complex

0.65 g (4.00 mmol) iron(III)-chloride were dissolved in 25 ml THF and2.56 g (12.00 mmol) of ethyl (1-methyl-2-oxopiperidine-3-yl)(oxo)acetatewere added. After 40 min stirring time 1.21 g (12.00 mmol) triethylaminewas added and it was stirred for further 60 min at room temperature.Then 2.59 g 25% sodium methoxide solution (12.00 mmol) was addeddropwise, and the solution was stirred for another 2 hours. Theprecipitated salt was filtered and the filtrate was concentrated on arotary evaporator to dryness. The residue was dried for 1 day at 50° C.in a high vacuum. This gave 2.6 g product as a red solid.

IR (neat, cm⁻¹): 2939, 2863, 1724, 1610, 1573, 1538, 1480, 1402, 1364,1308, 1256, 1219, 1195, 1101, 1079, 1060, 1016, 959, 920, 892, 858, 811,764, 724, 692.

Elemental analysis: C, 51.62%, H, 6.23%, N, 5.90%.

Fe-content: 8.2% [m/m].

Example 31 Tris-(3-acetyl-1-methylpiperidin-2-one)-iron(III)-complex

0.34 g (2.10 mmol) iron(III)chloride were dissolved in 100 ml of ethanoland 1.34 g (6.30 mmol) of 3-acetyl-1-methylpiperidin-2-one was added.1.33 g 25% sodium methoxide solution (6.13 mmol) were diluted with 10 mlethanol and added dropwise to the reaction solution. The reactionsolution was stirred for 30 min and then filtered off. The filtrate wasconcentrated on a rotary evaporator to dryness and the residue was takenup in 50 ml of dichloromethane. The solution was again filtered, thedichloromethane was removed on a rotary evaporator and the residue wasdried for 2 days at 50° C. under high vacuum. This gave 1.2 g product asa dark red solid.

IR (neat, cm⁻¹): 2927, 2855, 1559, 1462, 1399, 1303, 1254, 1202, 1181,1082, 992, 921, 887, 856, 757, 707, 626.

Elemental analysis: C, 49.63%, H, 6.43%, N, 7.23%.

Fe-content: 9.80% [m/m].

Example 32 Tris-(ethyl4-(dimethylamino)-2,4-dioxobutanoate)-iron(III)-complex

0.58 g (3.56 mmol) iron(III)chloride were dissolved in 80 ml THF and2.00 g (10.69 mmol) of ethyl 4-(dimethylamino)-2,4-dioxobutanoate wasadded. After 40 min stirring time 1.07 g (10.69 mmol) triethylamine wasadded and the mixture was stirred for another 60 min at roomtemperature. Then 2.31 g 25% sodium methoxide solution (10.69 mmol) wasadded dropwise and the solution was stirred for another 2 hours. Theprecipitated salt was filtered and the filtrate was concentrated on arotary evaporator to dryness. The residue was dried for 1 day at 50° C.in a high vacuum. This gave 2.0 g product as a red solid.

IR (neat, cm⁻¹): 2927, 1719, 1616, 1575, 1501, 1433, 1404, 1362, 1235,1174, 1136, 1019, 944, 924, 767, 742, 652.

Elemental analysis: C, 45.83%, H, 5.82%, N, 6.83%.

Fe-content: 8.54% [m/m].

Example 33 Tris-(1-(morpholin-4-yl)butane-1,3-dione)-iron(III)-complex

To a solution of 3.17 g (18.50 mmol) 1-(morpholin-4-yl)butane-1,3-dionein 40 ml of ethanol, a solution of 1.00 g (6.17 mmol) iron(III)chloride(anhydrous) in 10 ml ethanol was added dropwise. Then 6.22 g (74.00mmol) of sodium bicarbonate was added in portions. After 1.5 h stirringat room temperature, the reaction mixture was filtered, washed with 10ml of ethanol, the filtrate evaporated on a rotary evaporator, and theresidue was dried overnight in an oven at 50° C. This gave 3.50 g ofbrown solid.

IR (neat, cm⁻¹): 2961, 2896, 2854, 1595, 1553, 1509, 1476, 1443, 1362,1299, 1273, 1244, 1193, 1110.

Fe-content: 9.62% [m/m].

Example 34 Tris-(N-(2-methoxyethyl)-3-oxobutanamide)-iron(III)-complex

To a solution of 1.47 g (9.25 mmol) N-(2-methoxyethyl)-3-oxobutanamidein 15 ml of ethanol, a solution of 0.5 g (3.08 mmol) iron(III)chloride(anhydrous) in 5 ml of ethanol was added dropwise. Then 1.56 g (18.50mmol) of sodium bicarbonate was added in portions. After stirring for 1h at room temperature, the reaction mixture was filtered, washed with 10ml of ethanol, the filtrate was evaporated on a rotary evaporator andthe residue was dried overnight in an oven at 50° C. This gave 1.51 g ofbrown oil.

IR (neat, cm⁻¹): 3269, 2980, 2928, 2882, 2830, 1650, 1550, 1499, 1451,1410, 1275, 1192, 1117, 1092, 1017, 958.

Fe-content: 9.68% [m/m].

Example 35 Tris-(N-Cyclopropyl-3-oxobutanamide)-iron(III)-complex

To a solution of 2.61 g (18.50 mmol) N-cyclopropyl-3-oxobutanamide in 30ml of ethanol, a solution of 1.00 g (6.17 mmol) iron(III)chloride(anhydrous) in 10 ml ethanol was added dropwise. Then 3.11 g (37.00mmol) of sodium bicarbonate was added in portions. After stirring for 1h at room temperature, the reaction mixture was filtered, washed with 10ml of ethanol, the filtrate was evaporated and the residue was driedovernight in an oven at 50° C. This gave 2.57 g of brown solid.

IR (neat, cm⁻¹): 3245, 3088, 3008, 1549, 1493, 1453, 1405, 1334, 1275,1219, 1189, 1060, 1023, 981, 937.

Fe-content: 11.00% [m/m].

Example 36 Tris-(3-oxo-N-(propan-2-yl)butanamide)-iron(III)-complex

To a solution of 1.32 g (9.25 mmol) of 3-oxo-N-(propan-2-yl)butanamidein 15 ml of ethanol, a solution of 0.5 g (3.08 mmol) iron(III)chloride(anhydrous) in 5 ml ethanol was added dropwise. Then 1.56 g (18.50 mmol)of sodium bicarbonate was added in portions. After stirring for 2 h atroom temperature, the reaction mixture was filtered, washed with 10 mlof ethanol, the filtrate was evaporated and the residue was driedovernight in an oven at 50° C. This gave 1.30 g of a brown solid.

IR (neat, cm⁻¹): 3248, 3101, 2972, 2936, 2873, 1544, 1492, 1468, 1447,1365, 1321, 1265, 1187, 1171, 1129, 998, 968.

Fe-content: 11.22% [m/m].

Example 37 Tris-(N-(2-hydroxyethyl)-3-oxobutanamide)-iron(III)-complex

To a solution of 2.69 g (18.50 mmol) N-(2-hydroxyethyl)-3-oxobutanamidein 40 ml of ethanol, a solution of 1.00 g (6.17 mmol) iron(III)chloride(anhydrous) in 10 ml ethanol was added dropwise. Then 6.22 g (74.00mmol) of sodium bicarbonate was added in portions. After stirring for 2h at room temperature, the reaction mixture was filtered, washed with 10ml of ethanol, the filtrate was evaporated and the residue was driedovernight in an oven at 50° C. This gave 2.72 g of a brown solid.

IR (neat, cm⁻¹): 3259, 3110, 2946, 2875, 1552, 1498, 1451, 1405, 1360,1273, 1188, 1059, 1018, 955, 778.

Fe-content: 11.30% [m/m].

Example 38 Tris-(N-(3-hydroxypropyl)-3-oxobutanamide)-iron(III)-complex

To a solution of 1.47 g (9.25 mmol) N-(3-hydroxypropyl)-3-oxobutanamidein 20 ml of ethanol, a solution of 0.5 g (3.08 mmol) iron(III)chloride(anhydrous) in 5 ml of ethanol was added dropwise. Then 1.56 g (18.50mmol) of sodium bicarbonate was added in portions. After stirring for 2h at room temperature, the reaction mixture was filtered, washed with 10ml of ethanol, the filtrate was evaporated and the residue driedovernight in an oven at 50° C. This gave 1.80 g of brown solid.

IR (neat, cm⁻¹): 3270, 2939, 1551, 1500, 1407, 1270, 1188, 1008, 973,947, 777.

Fe-content: 10.05% [m/m].

Example 39 Tris-(N-(4-hydroxybutyl)-3-oxobutanamide)-iron(III)-complex

To a solution of 2.94 g (18.50 mmol) N-(4-hydroxybutyl)-3-oxobutanamidein 40 ml of ethanol, a solution of 1.00 g (6.17 mmol) iron(III)chloride(anhydrous) in 10 ml ethanol was added dropwise. Then 3.11 g (37.00mmol) of sodium bicarbonate was added in portions. After stirring for 2h at room temperature, the reaction mixture was filtered, washed with 10ml of ethanol, the filtrate was evaporated and the residue driedovernight in an oven at 50° C. This gave 2.72 g of a brown solid.

IR (neat, cm⁻¹): 3273, 2934, 2867, 1649, 1555, 1502, 1436, 1409, 1272,1188, 1053, 1027, 946, 778.

Fe-content: 9.36% [m/m].

Example 40 Tris-(N-(5-hydroxypentyl)-3-oxobutanamide)-iron(III)-complex

To a solution of 3.46 g (18.50 mmol) N-(5-hydroxypentyl)-3-oxobutanamidein 40 ml of ethanol, a solution of 1.00 g (6.17 mmol) iron(III)chloride(anhydrous)) in 10 ml ethanol was added dropwise. Then 3.11 g (37.00mmol) of sodium bicarbonate was added in portions. After stirring for 1h at room temperature, the reaction mixture was filtered, washed with 10ml of ethanol, the filtrate was evaporated and the residue was driedovernight in an oven at 50° C. This gave 3.51 g of brown solid.

IR (neat, cm⁻¹): 3255, 3109, 2932, 2862, 1558, 1500, 1433, 1407, 1274,1187, 1021, 949, 779.

Fe-content: 8.85% [m/m].

Example 41Tris-(N-(1-hydroxy-2-methylpropan-2-yl)-3-oxobutanamide)-iron(III)-complex

To a solution of 3.20 g (18.50 mmol)N-(1-hydroxy-2-methylpropane-2-yl)-3-oxobutanamid in 40 ml of ethanol, asolution of 1.00 g (6.17 mmol) iron (III) chloride anhydrous was addeddropwise in 10 ml ethanol. Then 3.11 g (37.00 mmol) of sodiumbicarbonate was added in portions. After stirring for 1 h at roomtemperature, the reaction mixture was filtered, washed with 10 ml ofethanol, the filtrate evaporated and the residue dried overnight in anoven at 50° C. This gave 3.42 g of a brown solid.

IR (neat, cm⁻¹): 3286, 2972, 2927, 1593, 1550, 1498, 1446, 1411, 1363,1287, 1225, 1189, 1050, 962.

Fe-content: 9.17% [m/m].

Example 42Tris-(N-(2-hydroxyethyl)-N-methyl-3-oxobutanamide)-iron(III)-complex

To a solution of 2.94 g (18.50 mmol)N-(2-hydroxyethyl)-N-methyl-3-oxobutanamide in 30 ml of ethanol, asolution of 1.00 g (6.17 mmol) iron(III)chloride (anhydrous) in 10 mlethanol was added dropwise. Then 3.11 g (37.00 mmol) of sodiumbicarbonate was added in portions. After stirring for 1 h at roomtemperature, the reaction mixture was filtered, washed with 10 ml ofethanol, the filtrate was evaporated and the residue was dried overnightin an oven at 50° C. This gave 3.11 g of a brown solid.

IR (neat, cm⁻¹): 3371, 2975, 2930, 2884, 1638, 1561, 1517, 1494, 1436,1351, 1301, 1205, 1170, 1051, 958.

Fe-content: 9.61% [m/m].

Example 43 Tris-(N-(2-hydroxypropyl)-3-oxobutanamide)-iron(III)-complex

To a solution of 2.94 g (18.50 mmol) N-(2-hydroxypropyl)-3-oxobutanamidein 30 ml of ethanol, a solution of 1.00 g (6.17 mmol) iron(III)chloride(anhydrous) in 10 ml ethanol was added dropwise. Then 6.22 g (74.00mmol) of sodium bicarbonate was added in portions. After stirring for 2h at room temperature, the reaction mixture was filtered, washed with 10ml of ethanol, the filtrate was evaporated and the residue was driedovernight in an oven at 50° C. This gave 3.11 g of a brown solid.

IR (neat, cm⁻¹): 3281, 2973, 2925, 1552, 1501, 1454, 1409, 1377, 1272,1190, 1079, 1053, 951, 777.

Fe-content: 9.84% [m/m].

Example 44Tris-(N-(1-hydroxypropan-2-yl)-3-oxobutanamide)-iron(III)-complex

To a solution of 2.94 g (18.50 mmol) N-(2-hydroxypropyl)-3-oxobutanamidein 30 ml of ethanol, a solution of 1.00 g (6.17 mmol) iron(III)chloride(anhydrous) in 10 ml ethanol was added dropwise. Then 6.22 g (74.00mmol) of sodium bicarbonate was added in portions. After stirring for 2h at room temperature, the reaction mixture was filtered, washed with 10ml of ethanol, the filtrate was evaporated and the residue was driedovernight in an oven at 50° C. This gave 3.22 g of a brown solid.

IR (neat, cm⁻¹): 3259, 2973, 1551, 1494, 1451, 1409, 1270, 1189, 1158,1091, 1041, 962.

Fe-content: 9.57% [m/m].

Example 45Tris-(N-(1-hydroxybutan-2-yl)-3-oxobutanamide)-iron(III)-complex

To a solution of 3.21 g (18.50 mmol)N-(1-hydroxybutane-2-yl)-3-oxobutanamide in 30 ml of ethanol a solutionof 1.00 g (6.17 mmol) iron(III)chloride (anhydrous) in 10 ml ethanol wasadded dropwise. Then 6.22 g (74.00 mmol) of sodium bicarbonate was addedin portions. After stirring for 2 h at room temperature, the reactionmixture was filtered, washed with 10 ml of ethanol, the filtrate wasevaporated and the residue was dried overnight in an oven at 50° C. Thisgave 3.22 g of brown solid.

IR (neat, cm⁻¹): 3268, 2965, 2933, 2875, 1546, 1493, 1457, 1410, 1285,1188, 1049, 1000, 959, 775.

Fe-content: 9.39% [m/m].

Example 46Tris-(N-(2,3-dihydroxypropyl)-3-oxobutanamide)-iron(III)-complex

To a solution of 1.75 g (9.25 mmol)N-(2,3-dihydroxypropyl)-3-oxobutanamide in 20 ml of ethanol, a solutionof 0.5 g (3.08 mmol) iron(III)chloride (anhydrous) in 5 ml ethanol wasadded dropwise. Then 1.56 g (18.50 mmol) of sodium bicarbonate was addedin portions. After stirring for 1 h at room temperature, the reactionmixture was filtered, washed with 10 ml of ethanol, the filtrate wasevaporated and the residue was dried overnight in an oven at 50° C. Thisgave 1.80 g of a brown solid.

IR (neat, cm⁻¹): 3349, 2929, 1635, 15559, 1519, 1493, 1353, 1210, 1157,1099, 1044, 996, 956, 765.

Fe-content: 8.81% [m/m].

Example 47Tris-(1-(3-hydroxypiperidin-1-yl)butane-1,3-dione)-iron(III)-complex

To a solution of 3.43 g (18.50 mmol)1-(3-hydroxypiperidine-1-yl)butane-1,3-dione in 50 ml of ethanol, asolution of 1.00 g (6.17 mmol) iron(III)chloride (anhydrous) in 10 mlethanol was added dropwise. Then 1.56 g (18.50 mmol) of sodiumbicarbonate was added in portions. After stirring for 4 h at roomtemperature, the reaction mixture was filtered, washed with 10 ml ofethanol, the filtrate was evaporated and the residue was dried overnightin an oven at 50° C. This gave 3.51 g of a brown solid.

IR (neat, cm⁻¹): 3290, 2929, 2859, 1554, 1509, 1483, 1441, 1363, 1254,1228, 1206, 1143, 1072, 997, 953, 858, 760.

Fe-content: 8.73% [m/m].

Example 48Tris-(1-[4-(hydroxymethyl)piperidin-1-yl]butane-1,3-dione)-iron(III)-complex

To a solution of 3.68 g (18.50 mmol) of1-[4-(hydroxymethyl)piperidine-1-yl]butane-1,3-dione in 50 ml ofethanol, a solution of 1.00 g (6.17 mmol) iron(III)chloride (anhydrous)in 10 ml ethanol was added dropwise. Then 3.11 g (37.00 mmol) of sodiumbicarbonate was added in portions. After stirring for 2 h at roomtemperature, the reaction mixture was filtered, washed with 10 ml ofethanol, the filtrate was evaporated and the residue was dried overnightin an oven at 50° C. This gave 3.81 g of a brown solid.

IR (neat, cm⁻¹): 3334, 2916, 2858, 1555, 1511, 1485, 1445, 1366, 1268,1247, 1217, 1088, 1033, 979, 953, 760.

Fe-content: 8.39% [m/m].

Example 49Tris-(1-[3-(hydroxymethyl)piperidin-1-yl]butane-1,3-dione)-iron(III)-complex

To a solution of 3.68 g (18.50 mmol) of1-[3-(hydroxymethyl)piperidine-1-yl]butane-1,3-dione in 50 ml ofethanol, a solution of 1.00 g (6.17 mmol) iron(III)chloride (anhydrous)in 10 ml ethanol was added dropwise. Then 3.11 g (37.00 mmol) of sodiumbicarbonate was added in portions. After stirring for 1 h at roomtemperature, the reaction mixture was filtered, washed with 10 ml ofethanol, the filtrate was evaporated and the residue was dried overnightin an oven at 50° C. This gave 3.92 g of a brown solid.

IR (neat, cm⁻¹): 3350, 2922, 2858, 1555, 1510, 1485, 1440, 1366, 1259,1088, 1039, 995, 953, 760.

Fe-content: 8.27% [m/m].

Example 50Tris-(1-[2-(hydroxymethyl)piperidin-1-yl]butane-1,3-dione)-iron(III)-complex

To a solution of 3.68 g (18.50 mmol) of1-[2-(hydroxymethyl)piperidine-1-yl]butane-1,3-dione in 50 ml ofethanol, a solution of 1.00 g (6.17 mmol) iron(III)chloride (anhydrous)in 10 ml ethanol was added dropwise. Then 3.11 g (37.00 mmol) of sodiumbicarbonate was added in portions. After stirring for 2 h at roomtemperature, the reaction mixture was filtered, washed with 10 ml ofethanol, the filtrate was evaporated and the residue was dried overnightin an oven at 50° C. This gave 3.88 g of a brown solid.

IR (neat, cm⁻¹): 3358, 2914, 2854, 1554, 1509, 1484, 1445, 1370, 1311,1269, 1245, 1217, 1088, 1035, 978, 953, 759.

Fe-content: 8.37% [m/m].

Example 51Tris-(1-[(3S)-3-hydroxypyrrolidin-1-yl]butane-1,3-dione)-iron(III)-complex

To a solution of 3.17 g (18.50 mmol) of1-[(3S)-3-hydroxypyrrolidine-1-yl]butane-1,3-dione in 50 ml of ethanol,a solution of 1.00 g (6.17 mmol) iron(III)chloride (anhydrous) in 10 mlethanol was added dropwise. Then 3.11 g (37.00 mmol) of sodiumbicarbonate was added in portions. After stirring for 2 h at roomtemperature, the reaction mixture was filtered, washed with 10 ml ofethanol, the filtrate was evaporated and the residue was dried overnightin an oven at 50° C. This gave 3.23 g of a brown solid.

IR (neat, cm⁻¹): 3315, 2946, 1558, 1514, 1472, 1350, 1206, 1103, 1054,951, 875, 763.

Fe-content: 8.61% [m/m].

Example 52Tris-(1-[4-(2-hydroxyethyl)piperazin-1-yl]butane-1,3-dione)-iron(III)-complex

To a solution of 3.96 g (18.50 mmol) of1-[4-(2-hydroxyethyl)piperazine-1-yl]butane-1,3-dione in 80 ml of MeOH asolution of 1.00 g (6.17 mmol) iron(III)chloride (anhydrous) in 20 mlMeOH was added dropwise. Then 3.11 g (37.00 mmol) of sodium bicarbonatewas added in portions. After stirring for 2 h at room temperature, thereaction mixture was evaporated, the residue taken up in 100 mldichloromethane, stirred for 15 minutes, filtered, and the filtrate wasevaporated. The residue was taken up in 50 ml EtOH, evaporated again andthe resulting residue was dried over eight in the drying oven. This gave4.10 g of a brown solid.

IR (neat, cm⁻¹): 3365, 2914, 2809, 1591, 1554, 1509, 1480, 1443, 1369,1290, 1249, 1138, 1050, 983, 960, 876, 759, 673.

Fe-content: 7.89% [m/m].

Example 53Tris-(1-(4-methylpiperazin-1-yl)butane-1,3-dione)-iron(III)-complex

To a solution of 3.41 g (18.50 mmol) 1-(4-methyl-1-yl)butane-1,3-dionein 80 ml MeOH, a solution of 1.00 g (6.17 mmol) iron(III)chloride(anhydrous) in 20 ml MeOH was added dropwise. Then 3.11 g (37.00 mmol)of sodium bicarbonate was added in portions. After stirring for 2 h atroom temperature, the reaction mixture was evaporated, the residue takenup in 100 ml dichloromethane, stirred for 15 minutes, filtered, and thefiltrate was evaporated. The residue was taken up in 50 ml EtOH,evaporated again and the resulting residue was dried over eight in thedrying oven. This gave 3.52 g of a brown solid.

IR (neat, cm⁻¹): 2934, 2845, 2789, 1554, 1507, 1478, 1445, 1370, 1291,1257, 1235, 1142, 1092, 1072, 1000, 981, 959. 757.

Fe-content: 8.77% [m/m].

Example 54Tris-(N-(3-hydroxypropyl)-N-methyl-3-oxobutanamide)-iron(III)-complex

To a solution of 3.20 g (18.50 mmol)N-(3-hydroxypropyl)-N-methyl-3-oxobutanamide in 40 ml of ethanol, asolution of 1.00 g (6.17 mmol) iron(III)chloride (anhydrous) in 10 mlethanol was added dropwise. Then 3.11 g (37.00 mmol) of sodiumbicarbonate was added in portions. After stirring for 1 h at roomtemperature, the reaction mixture was filtered, washed with 10 ml ofethanol, the filtrate was evaporated and the residue was dried overnightin a drying oven at 50° C. This gave 3.31 g of a brown oil.

IR (neat, cm⁻¹): 3376, 2919, 1557, 1492, 1348, 1296, 1263, 1212, 1190,1051, 989, 955, 763.

Fe-content: 9.08% [m/m].

Example 55Tris-(N-(trans-4-hydroxycyclohexyl)-3-oxobutanamide)-iron(III)-complex

To a solution of 3.68 g (18.50 mmol)N-(trans-4-hydroxycyclohexyl)-3-oxobutanamide in 80 ml of ethanol, asolution of 1.00 g (6.17 mmol) iron(III)chloride (anhydrous) in 20 mlethanol was added dropwise. Then 6.22 g (74.00 mmol) of sodiumbicarbonate was added in portions. After stirring for 2 h at roomtemperature, the reaction mixture was filtered, washed with 10 ml ofethanol, the filtrate was evaporated and the residue was dried overnightin an oven at 50° C. This gave 3.81 g of a brown solid.

IR (neat, cm⁻¹): 3280, 2932, 2859, 1549, 1494, 1453, 1409, 1371, 1309,1265, 1187, 1055, 1014, 961, 941, 776.

Fe-content: 7.84% [m/m].

Example 56Tris-(N-(3-hydroxy-2,2-dimethylpropyl)-3-oxobutanamide)-iron(III)-complex

To a solution of 3.46 g (18.50 mmol)N-(3-hydroxy-2,2-dimethylpropyl)-3-oxobutanamide in 50 ml of ethanol, asolution of 1.00 g (6.17 mmol) of iron(111)chloride (anhydrous) in 15 mlethanol was added dropwise. Then 6.22 g (74.00 mmol) of sodiumbicarbonate was added in portions. After stirring for 4 h at roomtemperature, the reaction mixture was filtered, washed with 10 ml ofethanol, the filtrate was evaporated and the residue was dried overnightin an oven at 50° C. This gave 4.40 g of a brown solid.

IR (neat, cm⁻¹): 3289, 2963, 2872, 1554, 1502, 1450, 1410, 1265, 1190,1050, 1014, 948, 777.

Fe-content: 8.3% [m/m].

Example 57Tris-(1-[4-(dimethylamino)piperidin-1-yl]butane-1,3-dione)-iron(III)-complex

To a solution of 3.93 g (18.50 mmol) of1-[4-(dimethylamino)piperidin-1-yl]butane-1,3-dione in 80 ml MeOH, asolution of 1.00 g (6.17 mmol) iron(III)chloride (anhydrous) in 10 mlMeOH was added dropwise. Then 3.11 g (37.00 mmol) of sodium bicarbonatewas added in portions. After stirring for 2 h at room temperature, thereaction mixture was evaporated, the residue was taken up in 100 mldichloromethane, stirred for 15 minutes, filtered, and the filtrate wasevaporated. The residue was taken up in 50 ml EtOH, evaporated again andthe resulting residue was dried overnight in the oven. This gave 4.23 gof a brown solid.

IR (neat, cm⁻¹): 2940, 2858, 2769, 1593, 1553, 1509, 1482, 1448, 1372,1328, 1271, 1236, 1205, 1040, 957, 874, 758.

Fe-content: 7.97% [m/m].

Example 58Tris-(1-(4-methoxypiperidin-1-yl]butane-1,3-dione)-iron(III)-complex

To a solution of 3.69 g (18.50 mmol)1-(4-methoxypiperidin-1-yl]butane-1,3-dione in 80 ml MeOH, a solution of1.00 g (6.17 mmol) iron(III)chloride (anhydrous) in 10 ml MeOH was addeddropwise. Then, 3.11 g (37.00 mmol) of sodium bicarbonate was added inportions. After 1 h stirring at room temperature, the reaction mixturewas evaporated, the residue was taken up in 100 ml dichloromethane, 15min stirred, filtered, and the filtrate was evaporated. The residue wastaken up in 50 ml EtOH, evaporated again, and the resulting residue wasdried overnight in a drying oven. This gave 4.01 g of a brown solid.

IR (neat, cm⁻¹): 2944, 2825, 1634, 1557, 1511, 1452, 1376, 1317, 1271,1235, 1184, 1096, 1047, 1023, 959, 939, 759.

Fe-content: 8.42% [m/m].

Example 59Tris-(1-(2,6-dimethylmorpholin-4-yl]butane-1,3-dione)-iron(III)-complex

To a solution of 3.69 g (18.50 mmol)1-(2,6-dimethylmorpholine-4-yl]butane-1,3-dione in 40 ml of ethanol, asolution of 1.00 g (6.17 mmol) iron(III)chloride (anhydrous) in 10 mlethanol was added dropwise. Then, 3.11 g (37.00 mmol) of sodiumbicarbonate was added in portions. After stirring for 2 h at roomtemperature, the reaction mixture was filtered, washed with 10 ml ofethanol, the filtrate was evaporated and the residue overnight was driedin an oven at 50° C. This gave 3.92 g of a brown solid.

IR (neat, cm⁻¹): 2974, 2872, 1556, 1510, 1477, 1373, 1258, 1244, 1172,1138, 1116, 1082, 1050, 1002, 958, 759.

Fe-content: 8.10% [m/m].

Example 60 Tris-(N-(morpholin-4-yl)-3-oxobutanamide)-iron(III)-complex

To a solution of 3.44 g (18.50 mmol) N-(morpholine-4-yl)-3-oxobutanamidein 50 ml of ethanol, a solution of 1.00 g (6.17 mmol) iron(III)chloride(anhydrous) in 20 ml ethanol was added dropwise. Then 3.11 g (37.00mmol) of sodium bicarbonate was added in portions. After stirring for 2h at room temperature, the reaction mixture was filtered, washed with 10ml of ethanol, the filtrate was evaporated and the residue was driedovernight in an oven at 50° C. This gave 3.63 g of a brown solid.

IR (neat, cm⁻¹): 3209, 2854, 1569, 1518, 1430, 1366, 1335, 1265, 1204,1108, 1072, 1044, 975, 952, 869, 778, 703.

Fe-content: 8.34% [m/m].

Example 61Tris-(1-(4-hydroxypiperidin-1-yl)pentane-1,3-dione)-iron(III)-complex

For the solution of 5.54 g (27.8 mmol)1-(4-hydroxypiperidine-1-yl)pentane-1,3-dione in 45 ml of anhydrousethanol, a solution of 1.51 g (9.31 mmol) anhydrous iron(III)chloride in10 ml of anhydrous ethanol was added, followed by 4.67 g (55.6 mmol) ofsodium bicarbonate. After 6.5 h, the reaction mixture was filtered andthe solids discarded. The filtrate was freed from solvent on a rotaryevaporator and the residue was dried for 16 h in a vacuum oven. Thisgave 5.56 g of a brown-red solid.

IR (neat, cm⁻¹): 2932, 2870, 1588, 1551, 1509, 1444, 1382, 1366, 1314,1265, 1224, 1119, 1074, 978, 924, 832, 801, 764, 705, 661.

Fe-content: 8.26%

Example 62 Tris-(1-(morpholin-4-yl)pentane-1,3-dione)-iron(III)-complex

To a solution of 3.18 g (17.2 mmol) 1-(morpholine-4-yl)pentane-1,3-dionein anhydrous ethanol, a solution of 0.997 g (6.15 mmol) of anhydrousiron(III)chloride in 11 ml of anhydrous ethanol was added. Then, 3.11 g(37.0 mmol) sodium hydrogen carbonate was added and the reaction mixturewas stirred 4 hours. The solids were filtered off and discarded. Thefiltrate was evaporated in a rotary evaporator to dryness and theresidue was dried for 16 h in a vacuum oven. This gave 3.33 g of ared-brown solid.

IR (neat, cm⁻¹): 2964, 2851, 1591, 1551, 1510, 1473, 1439, 1380, 1315,1300, 1274, 1241, 1189, 1112, 1063, 1003, 929, 857, 801, 763, 706, 664,593.

Fe-content: 9.13% [m/m/].

Example 63 Tris-(N-Butyl-3-oxoheptanamide)-iron(III)-complex

60 mmol (11.96 g) N-butyl-3-oxoheptanamide and 20 mmol (3.24 g) FeCl₃(anhydrous) were dissolved in 110 ml ethanol (anhydrous), and 10.4 mlsodium methylate solution (30% m/m) added. It was stirred for 0.5 hoursand the reaction solution was filtered. The filtrate was concentrated ona rotary evaporator and the product was dried. This gave 13.7 g of thetitle compound.

IR (neat, cm⁻¹): 2956, 2930, 2871, 1717, 1656, 1558, 1500, 1435, 1376,1325, 1299, 1271, 1177, 1103, 1085, 1050, 994, 948, 894, 778, 682.

CHN-Elemental analysis: C, 59.26; H, 9.21; N, 6.12.

Fe-content: 7.39% [m/m]

Example 64Tris-(1-(4-Hydroxypiperidin-1-yl)-4-methylpentane-1,3-dione)-iron(III)-complex

90 mmol (19.2 g) 1-(4-hydroxypiperidine-1-yl)-4-methylpentane-1,3-dioneand 30 mmol (4.87 g) FeCl₃ (anhydrous) were dissolved in 150 ml ethanol(anhydrous) and 30 ml sodium ethylate solution (21% m/m) was added. Itwas stirred for 0.5 h and the reaction solution was filtered. Thefiltrate was concentrated on a rotary evaporator and the product wasdried in a vacuum oven at 50° C. This gave 19.8 g of the title compound.

IR (neat, cm⁻¹): 2927, 2866, 1550, 1513, 1443, 1372, 1312, 1265, 1225,1190, 1157, 1119, 1072, 1022, 980, 945, 882, 823, 808, 771, 714, 660,646.

CHN-Elemental analysis: C, 52.00; H, 7.79; N, 5.99.

Fe-content: 7.21% [m/m]

Example 65Tris-(N-(2-Hydroxyethyl)-N,4-dimethyl-3-oxopentanamide)-iron(III)-complex

90 mmol (17.93 g) N-(2-hydroxyethyl)-N,4-dimethyl-3-oxopentanamide and30 mmol (4.87 g), FeCl₃ (anhydrous) were dissolved in 150 ml ethanol(anhydrous) and 15 ml sodium methylate solution (30% m/m) was added. Itwas stirred for another 0.5 h and the reaction solution was filtered.The filtrate was concentrated on a rotary evaporator and the product wasdried in a vacuum oven at 50° C. This gave 20.7 g of the title compound.

IR (neat, cm⁻¹): 2966, 2926, 2859, 1714, 1627, 1550, 1517, 1479, 1460,1439, 1384, 1371, 1358, 1301, 1273, 1246, 1190, 1159, 1114, 1087, 1065,1051, 1019, 991, 947, 927, 884, 850, 774, 717, 682.

CHN-Elemental analysis: C, 44.04; H, 6.97; N, 6.33.

Fe-content: 7.79% [m/m]

Example 66Tris-(N,N-Dimethyl-2-oxocyclopentanecarboxamide)-iron(III)-complex

18 mmol (3.29 g) N,N-dimethyl-2-oxocyclopentanecarboxamide (purity >85%)and 6 mmol (0.925 g) FeCl₃ (anhydrous) were dissolved in 50 ml ethanol(anhydrous), and 3 ml sodium methylate solution (30% m/m) were added. Itwas stirred for 1 h and the reaction solution was filtered. The filtratewas concentrated on a rotary evaporator and the product was dried in avacuum oven at 50° C. This gave 3.9 g of the title compound.

IR (neat, cm⁻¹): 2945, 2882, 1735, 1635, 1555, 1491, 1466, 1451, 1411,1395, 1362, 1347, 1303, 1262, 1215, 1186, 1169, 1141, 1099, 1050, 1020,983, 946, 915, 903, 885, 834, 770, 754, 733, 694, 638.

Fe-content: 8.03% [m/m]

Example 67 Tris-(N-cyclopentyl-3-oxobutanamide)-iron(III)-complex

To a solution of 31.3 g (18.50 mmol) N-cyclopentyl-3-oxobutanamide in 40ml of ethanol, a solution of 1.00 g (6.17 mmol) iron(III)chloride(anhydrous) in 10 ml ethanol was added dropwise. Then 6.22 g (74.00mmol) of sodium bicarbonate was added in portions. After stirring for 2h at room temperature, the reaction mixture was filtered, washed with 10ml of ethanol, the filtrate was evaporated and the residue was driedovernight in an oven at 50° C. This gave 3.74 g of a brown solid.

IR (neat, cm⁻¹): 3256, 2956, 2869, 1550, 1491, 1450, 1409, 1357, 1265,1185, 1042, 1015, 951, 780.

Fe-content: 9.17% [m/m].

Example 68 Tris-(1-(pyrrolidin-1-yl)butane-1,3-dione)-iron(III)-complex

To a solution of 2.87 g (18.50 mmol)1-(pyrrolidine-1-yl)butane-1,3-dione in 40 ml of ethanol, a solution of1.00 g (6.17 mmol) iron(III)chloride (anhydrous) in 10 ml ethanol wasadded dropwise. Then 6.22 g (74.00 mmol) of sodium bicarbonate was addedin portions. After stirring for 2 h at room temperature, the reactionmixture was filtered, washed with 10 ml of ethanol, the filtrate wasevaporated and the residue was dried overnight in an oven at 50° C. Thisgave 3.41 g of a brown solid.

IR (neat, cm⁻¹): 2966, 2869, 1556, 1511, 1473, 1457, 1351, 1328, 1224,1206, 1117, 1080, 996, 971, 953, 761.

Fe-content: 10.16% [m/m].

Example 69 Tris-(methyl-N-(3-oxobutanoyl)-L-serinate)-iron(III)-complex

To a solution of 3.75 g (18.50 mmol) of methylN-(3-oxobutanoyl)-L-serinate in 50 ml of ethanol, a solution of 1.00 g(6.17 mmol) iron(III)chloride (anhydrous)) in 10 ml ethanol was addeddropwise. Then 3.11 g (37.00 mmol) of sodium bicarbonate was added inportions. After stirring for 2 h at room temperature, the reactionmixture was filtered, washed with 10 ml of ethanol, the filtrate wasevaporated and the residue was dried overnight in an oven at 50° C. Thisgave 4.45 g of a brown solid.

IR (neat, cm⁻¹): 3285, 2955, 1733, 1543, 1491, 1408, 1343, 1274, 1209,1186, 1146, 1077, 1054, 1029, 958, 779.

Fe-content: 8.02% [m/m].

Example 70Tris-(1-(4-acetylpiperazine-1-yl)butane-1,3-dione)-iron(III)-complex

To a solution of 3.92 g (18.50 mmol)1-(4-acetylpiperazine-1-yl)butane-1,3-dione in 80 ml MeOH, a solution of1.00 g (6.17 mmol) iron(III)chloride (anhydrous) in 20 ml MeOH was addeddropwise. Then 3.11 g (37.00 mmol) of sodium bicarbonate was added inportions. After stirring for 1 h at room temperature, the reactionmixture was evaporated, the residue taken up in 200 ml dichloromethane,stirred for 15 minutes, filtered, and the filtrate was evaporated. Theresidue was taken up in 50 ml EtOH, evaporated again and the resultingresidue was dried overnight in a drying oven. This gave 4.1 g of a brownsolid.

IR (neat, cm⁻¹): 2914, 1637, 1555, 1511, 1468, 1421, 1367, 1284, 1239,1172, 1046, 981, 958, 760.

Fe-content: 7.74% [m/m].

Example 71 Tris-(N-cyclohexyl-3-oxobutanamide)-iron(III)-complex

To a solution of 3.39 g (18.50 mmol) N-cyclohexyl-3-oxobutanamide in 40ml of ethanol, a solution of 1.00 g (6.17 mmol) iron(III)chloride(anhydrous) in 10 ml ethanol was added dropwise. Then 3.11 g (37.00mmol) of sodium bicarbonate was added in portions. After stirring for 2h at room temperature, the reaction mixture was filtered, washed with 10ml of ethanol, the filtrate was evaporated and the residue was driedovernight in an oven at 50° C. This gave 3.8 g of a brown solid.

IR (neat, cm⁻¹): 3282, 2928, 2854, 1552, 1488, 1448, 1408, 1315, 1278,1256, 1187, 1150, 1109, 1041, 975, 942, 781.

Fe-content: 8.81% [m/m].

Example 72 Tris-(methyl-N-(3-oxobutanoyl)glycinate)-iron(III)-complex

To a solution of 3.21 g (18.50 mmol) of methylN-(3-oxobutanoyl)glycinate in 40 ml of ethanol, a solution of 1.00 g(6.17 mmol) iron(III)chloride (anhydrous) in 10 ml ethanol was addeddropwise. Then 3.11 g (37.00 mmol) of sodium bicarbonate was added inportions. After stirring for 1 h at room temperature, the reactionmixture was filtered, washed with 10 ml of ethanol, the filtrate wasevaporated and the residue was dried overnight in an oven at 50° C. Thisgave 3.95 g of a brown oil.

IR (neat, cm⁻¹): 3343, 2955, 1739, 1543, 1495, 1409, 1365, 1284, 1179,1051, 1011, 988, 779.

Fe-content: 8.95% [m/m].

Example 73 Tris-(N-(2-methylpropyl)-3-oxobutanamide)-iron(III)-complex

To a solution of 2.90 g (18.50 mmol) N-(2-methylpropyl)-3-oxobutanamidein 40 ml of ethanol, a solution of 1.00 g (6.17 mmol) iron(III)chloride(anhydrous) in 10 ml ethanol was added dropwise. Then 3.11 g (37.00mmol) of sodium bicarbonate was added in portions. After stirring for 4h at room temperature, the reaction mixture was filtered, washed with 10ml of ethanol, the filtrate was evaporated and the residue was driedovernight in an oven at 50° C. This gave 3.49 g of a brown solid.

IR (neat, cm⁻¹): 3284, 3110, 2959, 2927, 2871, 1551, 1499, 1433, 1408,1271, 1188, 1156, 1102, 1018, 954, 940, 777.

Fe-content: 9.70% [m/m].

Example 74Tris-(N-(cyclopropylmethyl)-3-oxobutanamide)-iron(III)-complex

To a solution of 1.44 g (9.25 mmol)N-(cyclopropylmethyl)-3-oxobutanamide in 20 ml of ethanol, a solution of0.5 g (3.08 mmol) iron(III)chloride (anhydrous) in 10 ml ethanol wasadded dropwise. Then 1.56 g (18.50 mmol) of sodium bicarbonate was addedin portions. After stirring for 4 h at room temperature, the reactionmixture was filtered, washed with 10 ml of ethanol, the filtrate wasevaporated and the residue was dried overnight in an oven at 50° C. Thisgave 1.75 g of a brown solid.

IR (neat, cm⁻¹): 3270, 1549, 1498, 1431, 1407, 1265, 1187, 1165, 1096,1023, 951, 830, 778.

Fe-content: 9.89% [m/m].

Example 75 Tris-(ethyl4-(morpholin-4-yl)-2,4-dioxobutanoate)-iron(III)-complex

0.24 g (1.45 mmol) iron(III)chloride were dissolved in 20 ml THF and1.00 g (4.36 mmol) of ethyl 4-(morpholine-4-yl)-2,4-dioxobutanoate wasadded. After 40 min of stirring, 0.44 g (4.36 mmol) of triethylamine wasadded and allowed to stir for another 60 min at room temperature. Then4.6 g 6% sodium ethoxide solution (4.4 mmol) was added dropwise and thesolution was stirred for another 2 hours. The precipitated salt wasfiltered off and the filtrate was concentrated on a rotary evaporator todryness. The residue was dried 1 day at 50° C. in high vacuum. This gave0.8 g product as an orange solid.

IR (neat, cm⁻¹): 2978, 2923, 2863, 1704, 1610, 1568, 1511, 1442, 1375,1300, 1275, 1246, 1138, 1111, 1062, 1018, 946, 860, 759, 722, 651.

Elemental analysis: C, 48.54%, H, 5.8%, N, 5.48%.

Fe-content: 6.9% [m/m].

Example 76 Tris-(ethyl N-(3-oxobutanoyl)-L-alaninate)-iron(III)-complex

To a solution of 3.72 g (18.50 mmol) of ethylN-(3-oxobutanoyl)-L-alaninate in 40 ml of ethanol, a solution of 1.00 g(6.17 mmol) iron(III)chloride (anhydrous) in 10 ml ethanol was addeddropwise. Then 3.11 g (37.00 mmol) of sodium bicarbonate was added inportions. After stirring for 2 h at room temperature, the reactionmixture was filtered, washed with 10 ml of ethanol, the filtrate wasevaporated and the residue was dried overnight in an oven at 50° C. Thisgave 4.00 g of a brown oil.

IR (neat, cm⁻¹): 3348, 2981, 1733, 1658, 1589, 1539, 1490, 1448, 1411,1300, 1206, 1186, 1155, 1051, 965, 777.

Fe-content: 7.80% [m/m].

Example 77 Tris-(N-cyclobutyl-3-oxobutanamide)-iron(III)-complex

To a solution of 1.43 g (9.25 mmol) N-cyclobutyl-3-oxobutanamide in 20ml of ethanol, a solution of 0.5 g (3.08 mmol) iron(III)chloride(anhydrous) in 10 ml ethanol was added dropwise. Then 1.56 g (18.50mmol) of sodium bicarbonate was added in portions. After stirring for 2h at room temperature, the reaction mixture was filtered, washed with 10ml of ethanol, the filtrate was evaporated and the residue was driedovernight in an oven at 50° C. This gave 1.71 g of a brown solid.

IR (neat, cm⁻¹): 3280, 2978, 2943, 1546, 1488, 1408, 1274, 1187, 1156,1031, 970, 946, 779, 757.

Fe-content: 9.98% [m/m].

Example 78 Tris-(1-(azetidine-1-yl)butane-1,3-dione)-iron(III)-complex

To a solution of 1.30 g (9.25 mmol) 1-(azetidine-1-yl)butane-1,3-dionein 20 ml of ethanol, a solution of 0.5 g (3.08 mmol) ofiron(III)chloride (anhydrous) in 10 ml ethanol was added dropwise. Then3.11 g (37.00 mmol) of sodium bicarbonate was added in portions. Afterstirring for 2 h at room temperature, the reaction mixture was filtered,washed with 10 ml of ethanol, the filtrate was evaporated and theresidue was dried overnight in an oven at 50° C. This gave 1.58 g of abrown solid.

IR (neat, cm⁻¹): 2945, 2878, 1558, 1510, 1473, 1344, 1297, 1201, 1003,948, 753.

Fe-content: 11.13% [m/m].

Example 79 Tris-(ethyl1-(3-oxobutanoyl)-piperidine-4-carboxylate)-iron(III)-complex

To a solution of 2.23 g (9.25 mmol) of ethyl1-(3-oxobutanoyl)-piperidine-4-carboxylate in 30 ml of ethanol, asolution of 0.5 g (3.08 mmol) iron(III)chloride (anhydrous) in 10 mlethanol was added dropwise. Then 3.11 g (37.00 mmol) of sodiumbicarbonate was added in portions. After stirring for 2 h at roomtemperature, the reaction mixture was filtered, washed with 10 ml ofethanol, the filtrate was evaporated and the residue was dried overnightin an oven at 50° C. This gave 2.43 g of a brown solid.

IR (neat, cm⁻¹): 2957, 2931, 2862, 1724, 1639, 1555, 1511, 1485, 1446,1372, 1312, 1271, 1236, 1174, 1038, 973, 958, 760.

Fe-content: 6.67% [m/m].

Example 80Tris-(1-(4-Hydroxypiperidin-1-yl)-4-methoxybutane-1,3-dione)-iron(III)-complex

18 mmol (3.91 g) 1-(4-hydroxypiperidine-1-yl)-4-methoxybutane-1,3-dioneand 6 mmol (0.96 g), FeCl₃ (anhydrous) were dissolved in 80 ml ethanol(anhydrous) and 4 ml of sodium methoxide solution (30% m/m) was added.It was stirred for 1 h and the reaction solution was filtered. Thefiltrate was concentrated on a rotary evaporator and the product wasdried. This gave 4.36 g of the title compound.

IR (neat, cm⁻¹): 2928, 2824, 1727, 1597, 1564, 1513, 1491, 1445, 1385,1331, 1265, 1227, 1197, 1109, 1074, 1051, 1025, 990, 957, 845, 807, 765,723, 653.

Fe-content: 7.11% [m/m].

The invention claimed is:
 1. A medicament, containing iron (III) complexcompounds having the formula

or pharmaceutically acceptable salts thereof.
 2. The medicament of claim1 further comprising at least one physiologically compatible carrier orexcipient.
 3. A composition, containing iron (III) complex compoundshaving the formula

or pharmaceutically acceptable salts thereof, in combination with atleast one further medicament which acts on iron metabolism.
 4. Acomposition, containing iron (III) complex compounds having the formula

or pharmaceutically acceptable salts thereof.
 5. An iron (III) complexcompound having the formula

or pharmaceutically acceptable salts thereof.